The transcription factor MITF in RPE function and dysfunction

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The transcription factor MITF in RPE function and dysfunction Xiaoyin Maa, Huirong Lia, Yu Chena, Juan Yanga, Huaicheng Chena, Heinz Arnheiterb, Ling Houa,∗ a Laboratory of Developmental Cell Biology and Disease, School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, and State Key Laboratory of Ophthalmology, Optometry and Vision Science, Wenzhou, 325003, China b National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892, USA

A R T I C LE I N FO

A B S T R A C T

Keywords: Microphthalmia Retinal pigment epithelium Retinal degeneration Melanocyte

Dysfunction and loss of the retinal pigment epithelium (RPE) are hallmarks of retinal degenerative diseases in mammals. A critical transcription factor for RPE development and function is the microphthalmia-associated transcription factor MITF and its germline mutations are associated with clinically distinct disorders, including albinism, microphthalmia, retinal degeneration, and increased risk of developing melanoma. Many studies have revealed new insights into central roles of MITF in RPE cell physiology, including melanogenesis, regulation of trophic factor expression, cell proliferation, anti-oxidant functions, and the visual cycle. In this review, we discuss the complex functional roles of MITF in RPE development, homeostasis, and retinal degeneration and touch upon key questions and challenges in neuroprotective strategies for retinal degenerative disorders associated with deficiencies in MITF or its many target genes.

1. General background The retinal pigment epithelium (RPE) of vertebrates constitutes a monolayer of cells that on its apical side abuts the photoreceptors of the retina and on its basal side the choriocapillaris. This location immediately suggests what critical functions the RPE plays in retinal physiology. Above all, the RPE, aided by a multilayer basement membrane, Bruch's membrane, provides a tight barrier between the highly vascularized choroid and the adjacent non-vascularized retinal layers, allowing for controlled bidirectional flow of water, ions, nutrients, and metabolites. In addition, it provides for trophic factors, has anti-oxidant properties, and participates in photoreceptor outer segment turnover and in the visual cycle (Fig. 1) (Simó et al., 2010; Strauss, 2005). Its most obvious property, however, is its pigmentation, which results from a dense accumulation of intracellular pigment granules (melanosomes) containing black eumelanin. Eumelanin, which broadly absorbs light at all visible wavelengths, serves primarily as a shield to prevent light from reaching deeper structures. This screening function is supported by an abundance of pigment cells in the choroid behind the RPE. These choroidal pigment cells, along with others in the ciliary body, the iris, and the Harderian gland, are all developmentally derived from precursors in the neural crest. The RPE, however, is derived from the optic neuroepithelium that also gives rise to the multiple layers of the retina (Bharti et al., 2006; Strauss, 2005). This fact has prompted

developmental biologists over many decades to analyze the molecular mechanisms underlying the initial specification of the optic neuroepithelium and its ultimate separation into retina, RPE, and optic stalk. This research, which involved in vivo genetic approaches mostly in model organisms, such as mice, as well as a variety of in vitro tests including the use of organotypic cultures in mice and chicks, revealed essential roles for many signaling pathways, transcription factors, and their target genes. One of these transcription factors, the microphthalmia-associated transcription factor MITF, is the focus of this review, and we discuss its role in development and in the adult in both mice and humans. We will also discuss how MITF or its target genes may be of potential use in therapeutic approaches to degenerative eye diseases, in which RPE abnormalities play critical roles. MITF research began over 75 years ago when a German researcher, Paula Hertwig, discovered mice with extremely small eyes among the descendants of an irradiated male mouse. She associated the phenotype with a novel mutation in a locus that she originally called m (Hertwig, 1942) but that later was renamed mi (Grüneberg, 1948). Mutant homozygotes did not only display small, abnormal eyes but were also entirely white, and, as found later, hearing-deficient (Tachibana et al., 1992), these latter two phenotypes due to the absence of neural crestderived melanocytes. Over the following decades, a large number of additional spontaneous alleles at this locus were found, but the underlying mutations became amenable to a molecular characterization

∗ Corresponding author. Laboratory of Developmental Cell Biology and Disease, State Key Laboratory of Ophthalmology, Optometry and Vision Science, Wenzhou Medical University, Wenzhou, 325003, China. E-mail address: [email protected] (L. Hou).

https://doi.org/10.1016/j.preteyeres.2019.06.002 Received 6 April 2019; Received in revised form 17 June 2019; Accepted 21 June 2019 1350-9462/ © 2019 Elsevier Ltd. All rights reserved.

Please cite this article as: Xiaoyin Ma, et al., Progress in Retinal and Eye Research, https://doi.org/10.1016/j.preteyeres.2019.06.002

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Fig. 1. Schematic diagram of RPE cellular functions that support retinal structure and function. The main functions of the RPE include: support of the visual cycle; phagocytosis of shed photoreceptor outer segments; secretion of trophic factors; transepithelial transport of nutrients, ions and water; anti-oxidant activities; absorption of light to protect photoreceptors from photooxidation. GCL, ganglion cell layer; IPL, inner plexiform layer; INL, inner nuclear layer; OPL, outer plexiform layer; ONL, outer nuclear layer; IS, inner segment; OS, outer segment; RPE, retinal pigment epithelium. Bar, 50 μm.

with Mitf being present at high levels both in neural crest-derived melanocytes and their precursors and in the RPE (Fig. 2) (Hodgkinson et al., 1993; Opdecamp et al., 1997; Nakayama et al., 1998). Mitf is further expressed at relatively high levels in osteoclasts, mast cells, kidney cells, and heart muscle cells and at lower levels in many other cell types (Arnheiter et al., 2005; Hu Frisk et al., 2017; Lu et al., 2014; Mehta et al., 2015). Numerous studies have shown that Mitf is critical for RPE specification and development. In fact, in the absence of Mitf, the presumptive RPE, though still discernible, fails to become pigmented, hyperproliferates, and then develops into a pseudostratified epithelium particularly

only with the cloning of the Mitf gene from transgenic insertional mutations (Hodgkinson et al., 1993; Hughes et al., 1994; Steingrímsson et al., 1994; Tachibana et al., 1992, 1994). For more details on the history of the discovery of Mitf — which serves as a prime example of the “triumph of serendipity” in research — we refer the reader to a previous review (Arnheiter, 2010). The cloning of Mitf revealed a gene encoding a novel member of a small subfamily of basic–helix–loop–helix–leucine zipper (bHLHZip) DNA-binding transcription factors that includes the TFE proteins TFEB, TFE3 and TFEC (Hemesath et al., 1994; Steingrímsson et al., 2002). The expression of these genes in vertebrates is found in many cell types,

Fig. 2. MITF expression in the developing RPE and neural retina histology in wild type and Mitf mutant. (A) Immunostaining for MITF was carried out in sections of eyes harvested from E12.5 C57BL/6J (WT) and Mitfmi-ew mouse embryos (which express non-functional MITF protein). MITF staining (green) is observed in the presumptive RPE in both wild type (white arrow) and mutant. In the mutant, however, MITF staining is decreased in the dorsal part where RPE cells hyperproliferate and the RPE thickens (red arrow). Bar, 100 μm. (B) Representative images of retinal histology of P21 WT and Mitfmi-vga9 mice. Mitfmi-vga9/mi-vga9 mice harbor a transgene array inserted into the promoter region of M-Mitf, which disrupts expression of all MITF isoforms. Note that Mitfmi-vga9 eyes lack pigmentation in the RPE layer and show severe retinal degeneration. GCL, ganglion cell layer; INL, inner nuclear layer; ONL, outer nuclear layer; RPE, retinal pigment epithelium. Bar, 50 μm. Fig. 2A is reproduced from Ou et al. (2013). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

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Fig. 3. Phenotypes of MITF mutations in humans and mice. (A, B) Clinical features of two independent COMMAD patients. (A) Compound heterozygous K307N/R318del mutation (A-MITF, GenBank: NP_ 937802.1, corresponding to K206N/R217del in MMITF, GenBank: NP_000239.1). (B) Compound heterozygous L312fs*11/R318G mutation (A-MITF, corresponding to L211fs*11/R217G in M-MITF). Note that for (A, B), A-MITF numbering is based on the (-6A) splice isoform but M-MITF numbering is based on the (+6A) splice isoform. Also note that based on the deletion of one of three consecutive AGA codons, it is not possible to determine precisely which arginine is deleted. (C–D) Phenotypes of a wildtype and a Mitfmi-vga9 homozygous mouse. (A) and (B) are reproduced from George et al. (2016), courtesy of Brian P. Brooks (NEI/NIH) and with permission from the American Journal of Human Genetics.

leucine zipper domain form dimers, and dimer formation is required for DNA binding. Most of the analysis of MITF protein is based on experiments with full length or truncated M-MITF, chromatin immunoprecipitation experiments, reporter assays, and the analysis of the crystal structure of the free and DNA-bound HLH-Zip or bHLH domain of MITF (Pogenberg et al., 2012). M-MITF binds so called E-box sequences of the type CANNTG with preference for the palindromic CACGTG and the nonpalindromic CATGTG sequences flanked with A or T (Cheli et al., 2010). Little if any information, however, is available on the binding specificities of the other MITF isoforms. Furthermore, although heterodimerization with TFEB, TFE3 and TFEC have been documented in vitro (Hemesath et al., 1994; Weilbaecher et al., 1998), there is no information yet on whether such heterodimers play any specific role in vivo. Full length mouse or human M-MITF contains 419 amino acids while the other isoforms are larger. It appears, however, that all isoforms are subject to further alternative splicing leading to many variants. A major alternative splicing event occurs with part of the downstream exon 6, called exon 6A, which, when spliced out, removes 6 residues (ACIFPT) upstream of the DNA binding basic domain. It appears that in most cells, both the +6A and -6A mRNAs [for short, (+) and (-) MITF] accumulate to about equal levels under normal conditions (Murakami et al., 2007), but their ratio may vary with MAPK signaling, as seen in melanoma cells (Primot et al., 2010). There is some evidence that (-) M-MITF binds DNA with a slightly reduced affinity compared to (+) M-MITF (Hemesath et al., 1994; Murakami et al., 2007; Pogenberg et al., 2012), but a clear functional difference has so far only been reported for experimentally expressed M-MITF in cultured RPE cells (Ma et al., 2018) (see below for more details). Another alternative splicing event characterized in some detail affects a subpart of exon 2, called exon 2B, which is lacking in ∼2–4% of the total amount of MITF mRNA in developing melanocytes (Debbache et al., 2012). Experimental removal or forced incorporation of exon 2B have minor effects on coat pigmentation in genetically sensitized mice (Bauer et al., 2009; Bismuth et al., 2008; Debbache et al., 2012) and its absence is associated with melanoma (Cronin et al., 2009). Whether the absence of exon 2B has any consequence for eye development or function, however, is not known. MITF has also been shown or suggested to be modified post-translationally by serine and tyrosine phosphorylation, sumoylation, acetylation, and ubiquitination. In vitro, phosphorylation of serine residues 73 and 409 is important for subsequent GSK3-mediated phosphorylation of neighboring serines. While phosphorylation at these sites is clearly linked to extracellular signaling, mutations at either serine 73 or 409, or serines 73 and 409 together, have only minor effects on coat color in vivo (Bauer et al., 2009; Debbache et al., 2012) and seemingly

in its dorsal part (Fig. 2) and later into a multilayered second retina expressing many retinal markers. The layers of this second retina, however, are inverted compared to the normal retina, suggesting that cellular re-specification is achieved without a change in apical-to-basal polarization. Subsequently, both primary and secondary retina degenerate (Fig. 2), and the eye remains non-functional (Bumsted and Barnstable, 2000; Nakayama et al., 1998; Nguyen and Arnheiter, 2000; Ou et al., 2013; Wen et al., 2016). It remains small likely because the optic fissure does not properly close, but what additional mechanisms and genes are involved in these failed morphological and subsequent degenerative events is not known in detail. In humans, MITF mutations have been found to be associated with Waardenburg Syndrome (WS) type IIa, the more severe Tietz albinismdeafness syndrome (TADS), and a novel syndrome called COMMAD (Fig. 3), which stands for Coloboma, Osteopetrosis, Microphthalmia, Macrocephaly, Albinism and Deafness (Tassabehji et al., 1994, 1995; George et al., 2016). These disorders primarily affect neural crest-derived melanocytes leading to pigment abnormalities in skin and eye and sensorineural deafness, but whether their severe forms may also affect the development of the RPE and lead to retinal degeneration as seen in Mitf mutant mice is not known. Furthermore, germline MITF mutations may also increase the risk for developing melanomas and renal carcinomas, and somatic mutations may influence the aggressiveness of established melanomas (Bertolotto et al., 2011; Cronin et al., 2009; Garraway et al., 2005; Hoek and Goding, 2010; Yokoyama et al., 2011). Importantly, while in mice heterozygosity for Mitf mutations does not usually lead to a visible phenotype, MITF heterozygosity in humans does, and so far only two individuals homozygous for an MITF mutation have been described (Pang et al., 2019; Rauschendorf et al., 2019). The most severe COMMAD syndrome is due to a combination of two distinct mutations present separately in the two parental alleles. 2. MITF gene structure and protein The human MITF gene, localized on the short arm of chromosome 3, spans approximately 229,000 bp from the start site of transcription to the poly(A) site. It contains at least nine isoform-specific promoters, each associated with its unique coding or non-coding exon, and 8 common exons, some of which subject to alternative splicing. This arrangement allows for the generation of many mRNA and protein isoforms, several of which (A-MITF, B-MITF, D-MITF, E-MITF, H-MITF, JMITF) are expressed in the RPE (Bharti et al., 2008; Hershey and Fisher, 2005). An additional isoform, M-MITF, which is the major isoform in neural crest-derived melanocytes, has also been found in adult human RPE and cultured RPE cells (Maruotti et al., 2012). A schematic representation of the structure of the MITF gene is shown in Fig. 4A (upper panel). The resulting proteins with their conserved bHLH3

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Fig. 4. Schematic diagram of MITF mutations in mice and humans.(A) The upper part of the figure shows the genomic organization of the gene. The boxes represent exons, with the numbers or letters written on top indicating the individual exons. Exons A, J, E, H, D, B, and M each have their own promoters. Exons A, J, E, H, and D are normally spliced to a site within exon B, leading to incorporation of a portion of exon B (termed exon 1B1b). The 3′ ends of exon B (or 1B1b) or exon M are spliced directly to the common exon 2A, resulting in a multitude of distinct mRNAs that give rise to multiple protein isoforms differing at their amino termini but sharing exons 2–9. M-MITF is the major isoform in neural crest-derived melanocytes while A-, D-, and H-MITF are the major isoforms in the developing RPE (Bharti et al., 2008). The sequences common to all isoforms comprise activation domains (blue), nuclear localization signals, and the DNA-binding basic-helix-loop-helix-leucine zipper domain (red). Indicated below the exons are the positions and characteristics of a selection of mouse Mitf mutations associated with ocular phenotypes (various degrees of depigmentation and microphthalmia), except for Mitfmi-bws, whose eye phenotype is restricted to a decreased c wave in the ERG, and Mitfmi-sp, which has no eye phenotype. (B) Schematic depiction of MITF mutations in people with Waardenburg syndrome (WS) and Tietz albinism-deafness syndrome (TADS) (indicated in black), and melanoma (indicated in red). Melanoma mutations are somatic, except for p.E318K, which is a germ line mutation. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Hamasaki, 1994. Steingrímsson et al., 1996). Nevertheless, a detailed histopathological analysis of the eyes is so far available only for a fraction of the mutations. To explain the differences in phenotypes associated with the different Mitf alleles, one has to consider the characteristics of each mutation. MITFMi-or protein, for instance, is unable to bind DNA but able to form homo- and heterodimers and hence able to act in a dominantnegative fashion, which is manifested in heterozygotes that show coat color dilution and white belly streaks, though no obvious eye phenotype. In contrast, MITFMi, though equally unable to bind DNA and capable of dimerization, produces heterozygotes that show at best a small white belly spot and a lighter colored tail. This apparent reduction in dominant-negative action is likely linked to the protein's increased cytoplasmic localization due to disruption of a nuclear localization signal (Nakayama et al., 1998; Takebayashi et al., 1996; and Fig. 5) (see below for more details on nuclear/cytoplasmic partitioning of MITF). Similarly, MITFmi-ew, which lacks part of the basic domain and cannot bind DNA efficiently (Hemesath et al., 1994), also partitions to the cytoplasm (Nakayama et al., 1998; and Fig. 5) and shows no dominant-negative activities in vivo. On the other hand, in Mitfmi-bws homozygotes, both wildtype Mitf mRNAs and Mitf mRNAs lacking exon

none on eye development. For further information, we refer the reader to recent reviews of the subject (Hartman and Czyz, 2015; Leclerc et al., 2017; Goding and Arnheiter, 2019).

3. Mitf mutant alleles in mice and humans Most of our knowledge on MITF in the RPE comes from studies in laboratory mice and chicks. To date, close to 40 different mutant alleles of Mitf, both spontaneous and molecularly engineered, have been described in mice, with all of them leading to either visible or at least biochemically detectable phenotypes (for a subset, see Table 1). Many of the spontaneous mutations are located in the bHLH-Zip domain (Fig. 4). Homozygosity for the alleles termed MitfMi, Mitfmi-ew, Mitfmivga9 , MitfMi-wh, MitfMi-or, Mitfmi-rw Mitfmi-enu198, Mitfmi-x39, and Mitfmi-ce leads to absence of coat pigmentation and to ocular pathologies that range from reduced eye size to severe microphthalmia and include absence of eye pigmentation. In contrast, homozygous MitfMi-ws mice have normal-sized, yet pink, eyes, and homozygous MitfMi-b and Mitfmivit mice have normal-sized eyes but show patchy RPE depigmentation, progressive loss of photoreceptor cells, and decreased ERG signals (Nakayama et al., 1998; Smith, 1992; Smith et al., 1994; Smith and 4

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Table 1 Examples of Mitf mutant alleles affecting eye development or functions in mice. Allele

Symbol mi-rw

Eye phenotype in homozygous mice

Molecular lesion

Reference#

Upstream genomic deletion Transgene insertion and 882-bp deletion Genomic deletion, lacks exon 2, 3 and 4 1408 bp deletion, deleting exon 4 p.A187_I212del, replaced by V Exon 2b missing in a portion of Mitf mRNAs p.D207G p.I212N p.R216K p.R217dela p.D222N

Bharti et al. (2008) Hodgkinson et al. (1993) Steingrímsson et al. (1994) Hallsson et al. (2000) Steingrímsson et al. (1994) Hallsson et al. (2000)

Red-eyed white VGA-9 White spot X39 Eyeless-white Black-and- White-spot

Mitf Mitfmi-vga9 MitfMi-ws MitfMi-x39 Mitfmi-ew Mitfmi-bws

Eyes small and red Eyes red and small Pink eyes of normal size Reduced eye size Very small eyes, eyelids do not open Reduced ERG C wave

Enu198 White Oak ridge Microphthalmia Vitiligo

MitfMi-enu198 MitfMi-Wh MitfMi-or MitfMi Mitfmi-vit

Minor microphthalmia, unpigmented eyes Eyes small and slightly pigmented Eyes small and red White coat; eyes small and red; Gradual depigmentation and slow progressive loss of photoreceptor cells

Brownish

MitfMi-b

Reduced eye pigment; normal eyes size, gradual retinal degeneration White coat; eyes pale (cloudy white) and small

Cloudy-eyed a

Mitf

mi-ce

p.G244E

Hallsson et al. (2000) Steingrímsson et al. (1994) Steingrímsson et al. (1994) Hodgkinson et al. (1993) Sidman et al. (1996); Smith (1992); Steingrímsson et al. (1994) Steingrímsson et al. (1996);

p.R263a

Steingrímsson et al. (1994)

One of 3 arginines in a row (215–217) deleted; # for a comprehensive review, see Steingrímsson et al. (2003).

with mutations at Kit, the receptor for KIT-ligand, which is known to activate the MAP kinase pathway, stimulate serine-73 phosphorylation, and regulate melanocyte but not RPE development (Wen et al., 2010), though it may influence retinal differentiation (Koso et al., 2007). It appears that the phenotype of the Mitfmi-bws allele and its interaction with Kit cannot simply be explained by the lack of exon 2B as the similar lack of exon 2B following a mutation in Ser73 does not show interactions with Kit. For a more detailed discussion of these observations, see (Wen et al., 2010). The Mitfmi-rw mutation leads to a deletion of the MITF exons 1H, 1D

2B accumulate (Hallsson et al., 2000). The corresponding protein without exon 2B likely retains DNA binding, dimerization, and nuclear localization, consistent with the observation that Mitfmi-bws homozygotes have normal-sized black eyes. Nevertheless, their electroretinogram (ERG) shows a decreased c wave (Möller et al., 2004), suggesting that the mutation still affects the function of the RPE and/or the retina. Interestingly, Mitfmi-bws homozygotes display white spotting of the coat, in contrast to the above mentioned mice in which exon 2B deletion was due to mutations in the codon for serine-73. Intriguingly, the presence of the Mitfmi-bws allele enhances the phenotype associated

Fig. 5. Intracellular localization analyses of wild type (WT), MitfMi and Mitfmi-ew proteins. (A) Diagram illustrating the basic-helix-loop-helix-leucine zipper domain and the amino acid sequence of M-MITF from residues 195 to 220 in wild type (WT) and the corresponding sequences in MitfMi or Mitfmiew . (B) WT, MitfMi or Mitfmi-ew were overexpressed in ARPE-19 cells, and MITF localization (red) was carried out by immunostaining. The MITF WT signal was detected in the nuclei, while the signals of MitfMi and Mitfmi-ew were located both in nuclei and cytoplasm. Bar, 10 μm. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

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homozygous individual is associated with a more severe WS phenotype than in his heterozygous parents (Rauschendorf et al., 2019). Homozygosity has also been described for p.R223H in two siblings with signs of WS2 but who also displayed chronic constipation suggestive of WS4 (Pang et al., 2019). The majority of WS- and TADS-associated MITF mutations are located in parts of the gene encoding the bHLH-Zip domain, while melanoma-associated MITF mutations preferentially lie in other domains (Fig. 4B). It is conceivable that the absence of Mitf target gene activation as normally seen with mutations in the DNA-binding domain may not be compatible with melanoma development and growth, and so melanoma-associated MITF mutations tend to lie outside the critical DNA-binding domain and instead might affect domains that either alter target gene preference or modulate interaction with protein partners (Grill et al., 2013). Nevertheless, with respect to RPE pathologies, little is known about downstream molecular mechanisms that might be impacted by different MITF mutations in humans. References: [1]:Yang et al. (2013); [2]: Wildhardt et al. (2013). [3]: Pingault et al. (2010); [4]: Rauschendorf et al. (2019);.[5]: Chen et al. (2010).; [6]: Grill et al. (2013);; [7]: Cortés-González et al. (2016); [8] Wang et al. (2018); [9]: Sun et al. (2017); [10]: Pang et al. (2019); [11]: George et al. (2016); [12]: Bertolotto et al. (2011); [13]: Cronin et al. (2009); [14]: Zhang et al. (2018).

and 1B, resulting in disruption of the downstream open reading frame. Nevertheless, reduced levels of MITFmi-rw protein are found in the RPE, likely reflecting aminoterminally truncated proteins predominantly translated from an internal AUG start codon (methionine 62) (Bharti et al., 2008). These truncated proteins are, however, not expressed at activity levels sufficient to support normal RPE development and pigmentation. While most other Mitf alleles are recessive, the dominant-negatively acting Mitf alleles are genetically semi-dominant in mice (producing a milder phenotype in heterozygotes and a more severe one in homozygotes). An unusual phenotype is seen with the dominant-negatively acting allele MitfMi-wh, due to a mutation of Ile212Asn in the DNAbinding domain, as this allele shows interallelic complementation with respect to its eye phenotype: Homozygous MitfMi-wh mice have small unpigmented eyes, similar to those seen in homozygous MitfMi mice, but MitfMi-wh/Mi compound heterozygotes have near normal-sized, though still unpigmented eyes (Konyukhov and Osipov, 1968; Steingrímsson et al., 2003). This phenomenon has tentatively been explained based on protein/DNA affinity measurements in conjunction with knowledge gained from the DNA/MITF cocrystal structure (Pogenberg et al., 2012). The Ile212Asn substitution in the MITFMi-wh protein leads to increased binding to non-specific DNA sequences when assayed in vitro, suggesting that in vivo, the mutated protein may access inappropriate target genes. In other words, MitfMi-wh may behave genetically as a neomorphic allele, which, when present in full (homozygous) dose, may lead to a more severe phenotype than when present in half dose in compound heterozygotes (Steingrímsson, 2010; Steingrímsson et al., 2003; Möller et al., 2004). It is not known, however, what target genes, if any, might be inappropriately expressed in MitfMi-wh mutant RPE. As mentioned above, Mitf is part of a family of genes that also includes Tfec, Tfeb, and Tfe3. Interestingly, studies in mice harboring single, dual and triple mutations in these genes did not show any phenotypic overlap associated with these mutations. In particular, mice homozygous for a null mutation in Tfec, which is expressed in the RPE, showed no obvious eye phenotype. Furthermore, neither Tfec−/ − ;MitfMi/Mi double mutants nor MitfMi-wh/Mi-wh;Tfec−/−;Tfe3−/− triple mutants showed visible eye phenotypes beyond what would be expected from the effects of the corresponding Mitf mutations. These results suggested that unlike for other bHLH-Zip family members like MYC/MAX/MAD, heterodimeric interactions between the MITF-TFE proteins are not essential in vivo (Steingrímsson et al., 2002), even though they can be demonstrated in vitro (Hemesath et al., 1994). MITF mutations have also been described in humans. Besides in the diseases mentioned above (WS, TADS, and COMMAD), human MITF mutations have been seen associated with nonsyndromic hearing loss and with melanoma and renal carcinoma (Table 2) (Bertolotto et al., 2011; George et al., 2016; Tassabehji et al., 1994, 1995; Yokoyama et al., 2011; Zhang et al., 2018). All mutations underlying the above disorders are inherited in an autosomal dominant way, but some are semidominant, such as c.33+5G > C which in the single reported

4. Regulation of MITF in RPE cells The activities of transcription factors such as MITF, which has multiple roles in a variety of cell types, likely need to be regulated precisely throughout the different stages of development and in adulthood. This may be particularly important for the RPE as its myriad functions in eye development and physiology may tolerate less uncontrolled fluctuations in MITF activity in vision-dependent organisms than, say, coat pigment cells whose malfunction may not immediately be life-threatening and which may be replenished from stem cells. This difference may perhaps explain why coat pigment cells express a single, predominant MITF isoform (M-MITF) while RPE cells express multiple isoforms, giving the latter the opportunity to compensate for the reduction or loss of one isoform with higher expression and activity levels of another (Bharti et al., 2012). Below we describe some of the signaling and transcriptional regulation of MITF operating in the RPE during development and in adulthood (schematically depicted in Fig. 6), discuss the regulation of intracellular localization, and highlight current gaps in our knowledge. 4.1. Signaling pathways 4.1.1. BMP signaling The developing eye and the tissues surrounding it express several members of the Bone morphogenetic proteins (BMPs) and their receptors (Chow and Lang, 2001). Some of them, such as BMP4 and

Table 2 Examples of MITF mutations associated with human disorders. Diseases

Mutations in MITF

WS2A

p.Y7C [1], p.Y10N [2], c.33+1G > A [3], c.33+5G > C (Splice) (Homozygous) [4], p.R110X [2], p.A111V [1], p.M138WfsX17 [3], c.442-2A > C [3], p.L148VfsX20 [3], p.T192fsX18 [5], p.E193DfsX2 [3], p.R203K [6], p.K206Q [6], c.634+1G > A [3], p.I212M [6], p.I212S [6], p.E213D [6], p.E213DfsX8 [3], p.R214X [6], p.R216S [7], p.R216K [6], p.R217G [1,6], p.R217I [2,6], p.R217del [1], p.I224S [6], c.710+1G > A [3], c.710+5G > T [3], p.S250P [6], p.Y253C [6], p.R255X [1], p.R259X [6], p.N269TfsX43 [3], p.E275GfsX37 [3], p.N278D [6], p.L283P [6], p.S298P [6], c.909G > A (Splice) [8], p.L354I [8], p.X420Y [9] p.R223H (Homozygous) [10] p.N210K, p.I212M, p.R217del, p.R217I [6] p.K206N, p.L211fsX11, p.R217G, p.R217del [11] p.E318K (germ line); p.E87R, c.A260G, p.L135V, p.L142F, p.G244R,, p.D380N (somatic) [12,13] p.E318K (germ line) [12] p.R240G [14]

WS4 TADS COMMAD Melanoma Renal carcinoma Non-syndromic hearing loss

X = indicates change to translational stop codon. The somatic mutations in melanomas are underlined. 6

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Fig. 6. MITF serves as the nexus between upstream regulatory pathways and downstream effects resulting from activation of specific target genes in the RPE. WNT/βcatenin, BMP, and FGF signaling regulate RPE cell development and differentiation by controlling positively or negatively the expression of MITF via the indicated transcription factors (ZEB1, PGC1α, β-catenin, PAX2, PAX6). The mechanism by which KL promotes Mitf expression in RPE cells is unknown. MITF can also interact with RPE-expressed transcription factors (e.g. PAX6, SOX9, and OTX2) to regulate downstream genes that in turn regulate various aspects of RPE physiology. For instance, TYR, TYRP1, PMEL17, and others are involved in melanin biogenesis; NF2 and miR204/211 in RPE development and differentiation; BEST1 in ion transport; PEDF in providing trophic support; PGC1α in serving an anti-oxidant function; RDH5 and RLBP1 in the visual cycle; and MSI2 and DAPL1 in cell proliferation.

expression of Mitf and the homeodomain protein gene Otx2 (see below). Upon β-catenin deletion in the presumptive RPE, the expression of Mitf and Otx2 is decreased and retina-specific gene expression is concomitantly induced in the transdifferentiating RPE (Westenskow et al., 2009). Conversely, as demonstrated in embryonic chick, experimental co-expression of constitutively active β-CATENIN and OTX2 in the presumptive retina induces ectopic Mitf expression (Westenskow et al., 2010). Chromatin immunoprecipitation (ChIP) and luciferase reporter assays further showed that β-CATENIN and TCF/LEF bind the promoters of both H-MITF and D-MITF, two of the isoforms expressed in the RPE, and stimulate the H-Mitf promoter (Fujimura et al., 2009), while Westenkow et al. (Westenskow et al., 2009) showed that β-CATENIN binds and activates the D-Mitf promoter. Whether the other RPE-expressed MITF isoforms are concordantly regulated, however, is not known.

BMP7, have been shown to be essential for eye development (Dudley et al., 1995; Furuta and Hogan, 1998; Luo et al., 1995). For instance, experimental increase in BMP levels in the presumptive optic stalk and neural retina region induce the expression of RPE markers including MITF, and the cells may eventually develop RPE-like features, including the appearance of pigment granules. In contrast, noggin-mediated inhibition of BMP signaling at the optic vesicle stage represses the formation of an RPE and induces neural retina specific gene expression in the presumptive RPE (Müller et al., 2007; Steinfeld et al., 2017). The BMP signaling pathway involves phosphorylation of SMAD proteins (SMAD1/5/8) which stimulate MITF expression, leading to RPE cell specification (Steinfeld et al., 2013). Consistent with these results, BMP4 is also required to induce the initial expression of MITF in melanocyte precursors differentiating from human embryonic stem (ES) cells (Yang et al., 2013). Clearly, these studies demonstrate that BMP signaling pathways are essential for the expression of MITF in both melanocytes and RPE cells. Nevertheless, the precise mechanisms by which BMP signaling controls MITF expression and whether all isoformspecific Mitf promoters are equally stimulated by BMPs are not known.

4.1.3. FGF signaling Fibroblast growth factors (FGF1and FGF2) are expressed in the surface ectoderm that overlies the developing eye vesicle, and their receptors, FGFR1 and FGFR2, are expressed in the developing optic vesicle (Tcheng et al., 1994; Wanaka et al., 1991). That FGF signaling is functionally important is based both on in vivo and in vitro experiments. Fgf1 and/or Fgf2 knockout mice have eye defects (Dono et al., 1998; Miller et al., 2000), and conditional knockout of Fgfr1 and Fgfr2 in the optic vesicle leads to ocular coloboma, optic nerve dysgenesis, and

4.1.2. WNT/β-catenin signaling RPE differentiation requires canonical WNT/β-catenin signaling (Steinfeld et al., 2013, 2017) through the activation of Frizzled receptors (Hou and Pavan, 2008). The WNT/β-catenin pathway is activated in differentiating mouse RPE cells and directly regulates the 7

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ectopic expression of MITF in the open optic fissure (Cai et al., 2013). In the chick, Fgf8 is highly expressed in the central area of the presumptive neural retina and application of FGF8 to the head mesenchyme just temporal to the optic vesicle at embryonic stages 8–14 decreases the expression of MITF and converts the presumptive retinal pigment epithelium (RPE) into neural retina (Vogel-Höpker et al., 2000). In optic vesicle cultures from mice, exposure to FGF represses the expression of MITF and converts the presumptive RPE to neural retinal tissue (Nguyen and Arnheiter, 2000). These results indicate that local FGF signaling plays critical roles by inhibiting MITF expression and RPE cell differentiation, thereby favoring the development of a retina. Conceivably, by activating the MAPK/ERK pathway as shown in the chick (Galy et al., 2002), FGF might induce degradation of MITF protein. Such MAPK-mediated MITF degradation has originally been observed in melanoma cells (Wu et al., 2000), though this was not confirmed later, at least not in the assays undertaken (Wellbrock and Marais, 2005). Furthermore, it has also been shown in optic vesicle explants that addition of FGF suppresses MITF mRNA accumulation (Bharti et al., 2006). Undoubtedly, other factors are involved as well as it has been shown, for instance, that FGF also stimulates the expression of the transcription factor VSX2 (formerly called CHX10), which acts as a repressor for MITF expression (Horsford et al., 2005) (see below). A cross talk between FGF, in particular FGF9, and VSX2 has also been observed in vitro in optic vesicles generated from human pluripotent stem cells (Gamm et al., 2019).

the homozygous state (Glaser et al., 1994). A conditional mutation of Pax6 in the RPE alone interferes with pigmentation (Raviv et al., 2014) and a conditional mutation in the retina alone leads to absence of retinal precursors, though it still allows for amacrine interneurons to develop (Marquardt et al., 2001). Interestingly, on an Mitf mutant background, a heterozygous germline Pax6 mutation exacerbates the RPEto-retina transdifferentiation and PAX6 overexpression from a yeast artificial chromosome (Schedl et al., 1996) interferes with RPE-to-retina transdifferentiation in Mitf-deficient embryos (Bharti et al., 2012). This result was unexpected as PAX6 normally has a proretinogenic role and its lack in the developing RPE was thought to inhibit the Mitf-mediated RPE-to-retina transition, and not to promote it. The result is consistent, however, with the above mentioned loss of pigmentation following RPE-specific knockout of Pax6. Expression profiling in the developing RPE suggests that in the RPE, PAX6, together with MITF and its paralog TFEC, indirectly enhance WNT/β-CATENIN signaling and suppress retinogenic gene expression. Hence, PAX6 can either promote retinal or RPE development in a context-dependent manner (Bharti et al., 2012). The Pax6 paralog Pax2 is co-expressed with Pax6 in E12.5 mouse optic vesicles but at later stages is predominantly found in the optic stalk (Bäumer et al., 2003). Prolonged expression of PAX6 in the PAX2positive optic stalk leads to ectopic expression of Mitf and differentiation of this tissue into a pigmented RPE-like epithelium. Both PAX2 and PAX6 bind to the promoter region of human A-MITF (Bäumer et al., 2003) and PAX6 also directly regulates the expression of D-MITF in RPE cells through specific binding sites in the D-MITF promoter (Raviv et al., 2014). In humans, PAX6 heterozygosity leads to multiple ocular abnormalities including microphthalmia and coloboma (Deml et al., 2016). Mutations in PAX2 have been implicated in retinal colobomas, including the papillorenal syndrome (PAPRS, OMIM, 120,330) (Schimmenti, 2011). Whether these human pathologies also involve dysregulation of MITF, however, is not known.

4.2. Transcription factors MITF plays an essential role in survival, proliferation, and differentiation of RPE cells. Therefore, understanding the transcriptional regulation of Mitf will help us identify the transcriptional hierarchy that directs specification, differentiation, and function of the RPE. Here we discuss a selection of transcription factors known to play a role in eye development.

4.2.3. OTX2 The homeobox protein OTX2 is another important transcription factor in the RPE where it is colocalized with MITF (Martínez-Morales et al., 2003). Mutations in OTX2 can cause early onset retinal dystrophy (Henderson et al., 2009) and the specific knockout of Otx2 in mouse RPE induces retinal degeneration (Housset et al., 2013). Although there is no direct evidence to support that OTX2 can activate transcription of MITF in RPE cells, the WNT/β-catenin induction of MITF in RPE cells depends on OTX2 in vivo (Westenskow et al., 2010).

4.2.1. VSX2 VSX2 is a homeobox transcription factor that acts as an early marker of retinal development. Homozygous Vsx2or-J mutant mice display microphthalmia and a pronounced defect in the proliferation of neuroretinal progenitor cells (Burmeister et al., 1996). They also ectopically express MITF in the neuroretina (Horsford et al., 2005). On the other hand, ectopic expression of VSX2 in the developing RPE decreases the expression of Mitf, Tfec, and associated pigment markers, leading to a non-pigmented RPE (Rowan et al., 2004). Interestingly, Vsx2or-J/or−J;MitfMi/Mi double mutant mice show a markedly improved retinal phenotype, suggesting that overexpression of functional MITF in Vsx2or-J/ or−J retina is responsible for retinal hypoplasia in these mice and that retinal expression of functional VSX2 normally suppresses the expression of the different Mitf isoforms in this tissue (Bharti et al., 2008; Capowski et al., 2014; Horsford et al., 2005; Konyukhov and Sazhina, 1966; Rowan et al., 2004). Nevertheless, it is likely that other pathways are involved as well. In fact, VSX2 binds and suppresses multiple genes of the WNT pathway and a functional null mutation in Vsx2 leads to activation of WNT signaling in the optic vesicle (Capowski et al., 2016). Therefore, it is conceivable that VSX2 not only suppresses Mitf transcription directly but also indirectly by inhibiting WNT/β-catenin signaling.

4.2.4. ZEB1 ZEB1 (zinc finger E-box binding homeobox-1), along with other factors such as TWIST1, suppresses epithelial specification genes and so promotes epithelial-to-mesenchymal transition (EMT). Interestingly, upon retinal detachment or experimental dissociation of the RPE, RPE cells start to express Zeb1, downregulate A-Mitf, lose pigmentation, proliferate, and undergo EMT. This process can be prevented in heterozygous Zeb1 mutant cells or by shRNA-mediated Zeb1 knockdown and reversed by re-enforcing cell-cell contacts (Liu et al., 2009). The upregulation of Zeb1 upon loss of RPE cell-cell contact involves translocation of the transcriptional activator TAZ and its cofactor TEAD1 from the cytoplasm to the nucleus and direct activation of the Zeb1 promoter (Liu et al., 2010). In humans, retinal detachment as well as surgical intervention can result in abnormal RPE proliferation known as proliferative vitreoretinopathy.

4.2.2. PAX6 and PAX2 The paired box/homeobox transcription factor PAX6 plays important roles in vertebrate eye development as it is responsible not only for the development of the retina but also for the formation of the cornea, lens and iris. Early in development, it is expressed throughout the optic vesicle and later in the above mentioned structures but also in the RPE (Bäumer et al., 2003). In mice, germline Pax6 null mutations cause microphthalmia in the heterozygous state and anophthalmia in

4.2.5. PGC1α PGC1α (peroxisome proliferator-activated receptor-gamma coactivator-1 alpha, PPRGC1A) is a transcriptional co-activator that potently regulates mitochondrial biogenesis and has anti-oxidant properties (StPierre et al., 2006). MITF directly regulates the expression of PGC1α in ARPE-19 cells (Hua et al., 2018). Conversely, in melanocytes, PGC1α 8

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melanocytes and melanoma cells. Target genes common to both RPE cells and neural crest-derived melanocytes are those directly involved in cell differentiation as manifested by melanosome biogenesis. As MITF is expressed in multiple, even non-pigmented cell types, however, both cell type-specific and common target genes have been identified. In the following we describe first the role of Mitf for pigmentation and then for some of the many additional features of the adult RPE (for a schematic depiction of the various roles of the RPE for retinal physiology, see Fig. 6).

activates the M-Mitf promoter and increases M-Mitf expression (Shoag et al., 2013). However, it is not known whether PGC1α can regulate the expression of MITF in RPE cells. 4.3. Other regulatory genes in the RPE The Klotho (Kl) gene was first described as a putative anti-aging gene (Kuro-o et al., 1997). Interestingly, Kl−/− mice display RPE cell dysfunction and retinal degeneration (Kokkinaki et al., 2013). Overexpression of KL in RPE cells promotes, and knockdown decreases, Mitf expression (Kokkinaki et al., 2013). In mice, the LIM homeodomain transcription factor LHX2 (LIM homeobox 2) is also required for Mitf expression during RPE development. In the Lhx2−/− optic vesicle, the activation of the BMP signaling pathway fails to initiate the expression of Mitf, suggesting that Lhx2 is required for the BMP signaling-dependent Mitf expression (Yang et al., 2014; Yun et al., 2009). The TGFβ family member activin also promotes the expression of RPE cell markers including MITF (Fuhrmann et al., 2000). Whether regulatory mechanisms shown to work in neural crest-derived pigment cells, such as those involving KIT, EDNRB, SOX10, PAX3, or non-coding RNAs (Hou and Pavan, 2008; Goswami et al., 2015), might also operate in the RPE has not so far been thoroughly explored, however.

5.1. Role of Mitf in RPE pigmentation Eumelanin is a black, light-absorbing biopolymer that is derived from the amino acid tyrosine and manufactured in melanosomes, a lysosome-related organelle. The biosynthetic process of melanin involves a set of genes including Tyrosinase (Tyr), Tyrosinase-related protein-1 (Tyrp1) and Dopachrome tautomerase (Dct), all of which sharing in their regulatory regions a common MITF binding motif called M-box. In cutaneous neural crest-derived melanocytes of mice, Mitf-dependent transcription of these genes follows a strict temporal sequence, with the gene encoding the rate-limiting enzyme TYR being expressed last, thus allowing for pigmentation only after birth. In the RPE, however, pigmentation is seen already at E11.5, concomitant with earlier and overlapping expression of these genes. In Mitf deficient mice, neither the RPE nor the choroid is pigmented, with the important difference that RPE cells survive but neural crest-derived melanocytes succumb. While in both cell types, Dct may initially be turned on in the absence of MITF, it remains expressed in RPE cells but cannot be found in places where neural crest-derived melanocytes are normally expected; Tyrp1 and Tyr expression, however, is absent in both cell types. Another difference between these two cell types concerns the structural aspect of the melanosomes, which in RPE are larger than in neural crest-derived melanocytes, though whether this difference is physiologically relevant is not known. Melanin protects photoreceptors from light damage (Wolkow et al., 2014) and may have anti-oxidant functions (Kaczara et al., 2012; Kirkwood, 2009; Sparrow et al., 2010). Interestingly, one of the precursors of melanin, L-DOPA, plays an independent role in the proper naso-temporal wiring of the retina (Lavado et al., 2006). Nevertheless, whether RPE melanin has any selective role in retinal function and vision is currently not known as an in vivo model, in which melanin would be entirely and selectively missing in an otherwise normal RPE without also missing in choroidal, ciliary body or iris melanocytes, does apparently not exist.

4.4. Regulation of intracellular localization As mentioned above, mutant MITF proteins may show increased accumulation in the cytoplasm, but until recently, relatively little was known about the regulation of the nuclear/cytoplasmic distribution of wildtype MITF. It has now been shown that the bHLH-Zip domain of MMITF harbors three karyophilic signals spanning residues 197–206, 214–217 and 255–265 that function regardless of whether MITF is in dimeric or monomeric form (Fock et al., 2019). Consistent with previous result, overexpression of MITFmi-ew or MITFMi, both lacking karyophilic sites, in ARPE-19 cells show an enhanced cytoplasmic localization compared to the near exclusive nuclear localization seen with wildtype M-MITF (Fig. 5). While M-MITF is thus predominantly nuclear under normal conditions, MITF isoforms containing exon 1B1b (the exon that is included in all major RPE-expressed isoforms) are subject to nutrient- and mTORregulated cytoplasmic retention in ARPE-19 cells as well as heterologous cells. Guided by experiments with the related TFEB and TFE3, the presence of an SR-QL motif in exon 1B1b allows for interaction with RAG proteins, bringing MITF to lysosomes via a RAG/mTORC1 complex and leading to MITF phosphorylation at Ser173 (numbering according to M-MITF) and interaction with 14-3-3 proteins. Nuclear export was assessed by using the inhibitor leptomycin-B. These studies revealed that nuclear export of M-MITF involves MAPK/ERK-mediated phosphorylation of Ser73 which serves as a priming site for GSK3-mediated phosphorylation of Ser69 and activation of a nuclear export signal (residues 75–80 in M-MITF). Nevertheless, the MAPK/ERK pathway seems to be of lesser importance for nuclear export of isoforms containing exon 1B1b (Lu et al., 2010; Martina and Puertollano, 2013; Ngeow et al., 2018). It is likely, however, that both exon 1B1b containing isoforms and M-MITF, which lacks this exon, are constitutively cycling between cytoplasm and nucleus, though their flux through the nuclear import-export cycle may differ. It appears, however, that only the exon 1B1b-containing isoforms are subject to efficient and regulated cytoplasmic retention. Whether any of these mechanisms actually operate in the RPE in vivo remains to be shown. For details, we refer the reader to recent reviews of the subject (Puertollano et al., 2018; Yang et al., 2018; Goding and Arnheiter, 2019).

5.2. Mitf and the regulation of cell proliferation In mammals, RPE cells undergo a phase of rapid cell divisions during early development but remain nonproliferative during adult life (Bharti et al., 2006; Ma et al., 2017; Salero et al., 2012). Nevertheless, several human conditions exist in which RPE cells restart proliferation and/or migrate into the vitreous. They include proliferative vitreoretinopathy (PVR), malignant congenital hypertrophy of the RPE, RPE rips, and Vogt–Koyanagi–Harada (VKH) disease. RPE hyperproliferation is also seen following retinal injury or surgery (Chiba, 2014; Hiscott et al., 1999; Leiderman and Miller, 2009; Peiretti et al., 2006; Saika et al., 2008; Shields et al., 2009; Yepez et al., 2015). High levels of MITF act as a repressor of cell proliferation, for instance by regulating the levels of the cyclin-dependent kinase inhibitor P21 as seen in melanoma cells (Carreira et al., 2005). In the RPE, however, the differentially spliced isoforms of MITF, may have different antiproliferative activities, and so we need to consider in greater detail their regulation and function. As described above, all MITF isoforms come in at least two classes distinguished by the presence or absence of 6 aa upstream of the basic domain, called (+) and (-) MITF. Our previous work suggested that the

5. Roles of MITF in RPE cells Mitf exerts its functions in cell development and physiology by upor downregulating a set of target genes, most of which identified in 9

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counteracting the oxidative stress that is common to the pathogenesis of a variety of retinal diseases, including AMD and diabetic retinopathy (DR) (Tokarz et al., 2013; Volpe et al., 2018). The regulation of the antioxidant activity of RPE cells involves many pathways and factors, including, for instance, the nuclear factor erythroid 2 (NRF2)-related signaling pathways. In fact, Nrf2 knockout mice display AMD-like retinal alterations and exacerbation of neuronal dysfunction in diabetes (Tode et al., 2018; Xu et al., 2014). The anti-oxidant function in RPE cells also involves the glutathione (GSH) anti-oxidant system, microRNAs, and mitochondria (Cai et al., 2000; Datta et al., 2017; Lin et al., 2011). It has been demonstrated, for instance, that MITF increases the RPE's antioxidant activity in part by regulating the expression of the Peroxisome proliferator activated receptor gamma coactivator 1 α (PGC1α, encoded by PPRGC1A), a regulator of mitochondrial biogenesis that also controls the mitochondrial OXPHOS/anti-oxidant axis (Hua et al., 2018), which is critical for RPE metabolism and retinal homeostasis (Jarrett et al., 2008). Both retina and RPE are highly sensitive to oxidative stress including photo-oxidation and inflammation, which are exacerbated by mitochondrial dysfunction (Datta et al., 2017). Nevertheless, whether MITF is directly involved in protecting the retina from oxidative damage in vivo is largely unknown.

two classes might play different roles in RPE cells. Indeed, overexpression of (-) M-MITF, but not (+) M-MITF, in ARPE-19 cells led to inhibition of cell proliferation (Ma et al., 2018). Furthermore, only (-) M-MITF and not (+) M-MITF increased the levels of DAPL1, identified as a novel suppressor of cell proliferation in RPE cells and a susceptibility locus for age-related macular degeneration (AMD) (Grassmann et al., 2015; Ma et al., 2017). The increase in DAPL1 levels is due to the fact that (-) M-MITF directly stimulates the transcription of Musashi homolog-2 (MSI2), which negatively regulates the processing of the anti-DAPL1 microRNA miR-7 (Ma et al., 2017, 2018). Nevertheless, it is not known by which mechanisms the presence or absence of exon 6A differentially regulate MSI2 and whether this pathway is involved at all in the above mentioned disorders. Also, it is not known how exon 6A splicing is regulated in the RPE and whether the two classes of proteins play additional roles in RPE cells. 5.3. Mitf and trophic factors The RPE expresses a number of trophic factors with neuroprotective properties, among them Pigment epithelium derived factor (PEDF, also named serin protease inhibitor F1 or SERPINF1, serpin family F member 1), Brain-derived neurotrophic factor (BDNF), Nerve growth factor (NGF), and Ciliary neurotrophic factor (CNTF) (Barnstable and Tombran-Tink, 2004; Chen et al., 2019; Kanuga et al., 2002. Kociok et al., 1998; Ma et al., 2012; Polato and Becerra, 2016; Tombran-Tink et al., 1995). Of these, Pedf has been identified as a Mitf target gene in ARPE-19 cells (Ma et al., 2012) and melanoma cells (Dadras et al., 2015; Fernández-Barral et al., 2014). Nevertheless, PEDF levels are decreased in the RPE and the interphotoreceptor matrix area of Mitf−/− mice (Chen et al., 2019). Also, Pedf-deficient mice exhibit a higher risk of developing retinal vascular expansion, hyperoxia-mediated vessel obliteration, and neovascularization (Huang et al., 2008). Moreover, patients with adult onset macular degeneration (AMD) show a reduction in PEDF expression levels (Bhutto et al., 2006), while retinitis pigmentosa and advanced glaucoma patients also show a lower PEDF level in the aqueous humor (Ogata et al., 2004), perhaps provoked by reductions in MITF activities. The findings support a role for Mitfregulated PEDF in photoreceptor protection in vivo and prompted studies testing for the effects of therapeutic application of PEDF (see below).

5.6. Additional RPE functions controlled by Mitf In mice homozygous for Mitfmi-vit, the RPE shows a markedly reduced number of phagosomes, suggesting reduced photoreceptor outer segment turnover (Kosaras and Sidman, 1996; Smith et al., 1994). Autoradiographic and biochemical assessment of rod outer segments demonstrated that Mitfmi-vit homozygotes have a defect in the renewal of the outer segments of photoreceptor cells (Smith and Defoe, 1995). Several lines of evidence link abnormal RPE phagocytic function to degenerative diseases of the retina (Ferrington et al., 2016; Mustafi et al., 2011). Mutations in MYO7A, a gene encoding a myosin involved in phagocytosis, are associated with Usher Syndrome, a disorder characterized by hearing deficiency and vision loss (Weil et al., 1995). Mutations in the MER protooncogene tyrosine kinase (MERTK), also involved in phagocytosis, is associated with retinitis pigmentosa (Gal et al., 2000). Whether MITF regulates these genes directly in the RPE, however, is not known, and how MITF might affect the phagocytic activity of RPE cells remains to be determined. In addition to phagocytosis, MITF may also control the transepithelial transport through the RPE. For instance, MITF, SOX9 and OTX2 control the expression of BEST1 (bestrophin-1), an anion channel protein (Johnson et al., 2017) specifically expressed in the RPE (Masuda and Esumi, 2010). Furthermore, the expression levels of the Fe (+2) iron transporter NRAMP1 (Slc11a1) was found to be altered in RPE cells of Mitfmi-vit and MitfMi mice (Gelineau-van Waes et al., 2008). Excess accumulation of Fe (+2) iron in RPE cells can cause oxidative damage (Akeo et al., 2002) and iron overload in RPE and Bruch's membrane is involved in the pathogenesis of AMD. In sum, then, it appears that MITF controls many functions in the RPE that are involved in retinal physiology, and MITF deficiencies may have major consequences for retinal homeostasis and vision.

5.4. Mitf and regulation of the visual cycle Photoreception involves the photoconversion of 11-cis retinal bound to opsins on both cone and rod photoreceptors. Upon light exposure, 11-cis retinal is converted to all-trans retinal, dissociated from opsin, and eventually converted back to 11-cis retinal through a series of enzymatic steps referred to as the visual cycle (McBee et al., 2001), whereby the RPE serves as the principal site for 11-cis retinal regeneration. Of the RPE enzymes involved in the visual cycle, retinol dehydrogenase-5 (RDH5), retinaldehyde binding protein-1 (RLBP1, also known as CRALBP), and the retinoid isomerohydrolyse RPE65 are encoded by genes stimulated by MITF (Wen et al., 2016). Indeed, mutations in these genes are responsible for a number of retinal disorders in humans, including Leber congenital amaurosis (LCA), retinitis pigmentosa (RP), retinitis punctata albescens and fundus albipunctatus (Thompson and Gal, 2003). In the mouse, Rlbp1 deficiency leads to Mopsin mislocalization, M-cone loss, and impaired cone-driven light responses and visual behavior (Xue et al., 2015). Conceivably, then, some forms of retinal degeneration may also be brought about by alterations in the activity of MITF on these visual cycle genes.

6. The potential therapeutic value of MITF and its target genes in RPE disorders and retinopathies As outlined above, RPE abnormalities are associated with several forms of retinal degeneration. Regardless of the underlying cause of the RPE pathology, one approach to intervene in the pathogenesis of retinal degeneration might be to replace the faulty RPE with healthy RPE cells and so restore full functionality of the RPE. Another approach might be based on the recognition that many of the neuroprotective functions of the RPE, including supplying trophic factors, protecting cells from oxidative damage, and supporting the visual cycle, are all under the control of MITF, and that at least some forms of retinal degeneration

5.5. Mitf and anti-oxidant functions An important function of the RPE is its antioxidant activity 10

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Fig. 7. Diagram illustrating the functional roles of MITF in RPE cells and the protein's suggested mechanisms for protection of photoreceptors. Under normal conditions (left), MITF regulates RPE physiology through its target genes as indicated in Fig. 6 . For instance, by regulating PEDF, it has neurotrophic and neuroprotective activities for photoreceptors; by regulating RDH5 and CRALBP, it affects the visual cycle; by regulating the expression of PGC1α, it promotes mitochondrial biogenesis and the anti-oxidant capacity of RPE cells; by regulating melanogenic genes, it induces pigmentation; and by regulating the expression of DAPL1 through MSI2, it keeps adult RPE cells quiescent. When MITF is dysfunctional (right side), these physiologically important outputs are reduced or lost entirely, which eventually may lead to photoreceptor degeneration.

So far, iPSC-derived RPE cell sheets have been optimized to meet strict clinical use requirements (Sharma et al., 2019). In major histocompatibility complex (MHC)-matched monkey models, transplantation of iPSC-RPE allografts has been performed safely with no signs of rejection (Sugita et al., 2016), and a clinical trial involving an autologous transplantation of iPSC-RPE to treat age-related macular degeneration (AMD) in humans has been performed by the RIKEN Institute, Japan (Kimbrel and Lanza, 2015; Mandai et al., 2017). To date, however, these approaches are still experimental and full restoration of retinal function has not yet been reported.

may therefore be causally linked to abnormalities in MITF (Fig. 7). Hence, one might think of using MITF or its target genes rather than intact RPE cells for therapeutic intervention. In the following, we will briefly outline these two different approaches.

6.1. Cell therapy (RPE transplantation) Cell replacement therapies aim to supplant lost or defective host RPE cells with healthy RPE cells that match authentic RPE cells in morphology, cell biology, and protective function for the retina. Both ES cells and induced pluripotent stem cells (iPSC) are suitable for the production of differentiated RPE cells (da Cruz et al., 2018; Jin et al., 2019; Jones et al., 2017; Kashani et al., 2018; Mandai et al., 2017; Nazari et al., 2015; Schwartz et al., 2012, 2015). In principle, heterologous wildtype cells could be used as the starting material, with the potential complication that any transplantation will likely be allogeneic. The iPSC technology has the added benefit that the starting material could be derived from the very patient selected for treatment, affording a syngeneic transplantation, but with the caveat that genetic or epigenetic alterations that may be responsible for the eye disorder in the first place may also be carried in the syngeneic cells. The availability of genetic engineering technologies including the CRISPR/Cas9 gene editing methods may help to correct pathogenic mutations determined to be causally involved in the disorder, in particular if only one mutation, or a very small number of mutations, is responsible. Nevertheless, given that RPE cells are strictly dependent on Mitf for specification, proliferation, and differentiation, a thorough knowledge of Mitf and its target gene regulations seems important to guarantee successful derivation of RPE cells. For a deeper discussion of the respective approaches to replace faulty RPE cells using endogenous repair mechanisms or ES cells and iPSCs, we refer the reader to a previous review (Bharti et al., 2011).

6.2. Trophic factors Based on results obtained in model organisms, of the above mentioned Mitf-regulated trophic factors, PEDF is a promising candidate for therapeutic interventions in humans. Intraocular injection of recombinant human PEDF or its peptides significantly protected photoreceptor cells from death both in mice harboring mutations in genes associated with retinal degeneration (Pde6brd1 or rds, now named Prph2Rd2, and Rd10) and in light-induced retinal degeneration models (Cao et al., 2001; Cayouette et al., 1999; Kenealey et al., 2015; Hernández-Pinto et al., 2019). A partial rescue can also be achieved by the addition of exogenous PEDF or a bioactive PEDF peptide composed of 17 residues (PEDF 17-mer) to explant cultures (Hernández-Pinto et al., 2019). Remarkably, application of eye drops containing the PEDF 17-mer to the eyes of Mitf-deficient mice also partially corrected the retinal dysfunction (Chen et al., 2019). Moreover, overexpression of PEDF in transgenic mice was able to inhibit retinal inflammation and neovascularization (Park et al., 2011). Conceivably, Mitf controls a number of different neuroprotective factors concordantly. Hence, it may eventually be beneficial to combine several factors in attempts to treat retinal degenerations. 11

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cells (Bharti et al., 2011; May-Simera et al., 2018). Nevertheless, we have to keep in mind that RPE cells may not be the only pigmented cells playing a role in retinal physiology and pathology, as the eye also contains large numbers of neural crest-derived pigment cells in choroid, iris, and ciliary body. Interestingly, melanocytes from people with lighter skin and/or hair color as well as albino mice secrete higher levels of fibromodulin, a protein that promotes neovascularization in the eye (Adini et al., 2014). This observation might partially explain the higher frequency of wet AMD in individuals of European descent compared to those of African or Asian descent (Adini et al., 2014; Vanderbeek et al., 2011). Also, the choroidal thickness is decreased in vitiligo patients (a disorder characterized by an immunemediated patchy demise of pigment cells in skin) (Demirkan et al., 2018). Furthermore, Mitfmi-bw mice, in which a normally pigmented RPE is combined with a lack of neural crest-derived melanocytes, show an abnormal choroidal vasculature and a thinner choroid (Shibuya et al., 2018). In any event, it may become important to explore whether there are functional interactions between RPE cells and neural crest-derived melanocytes, in other words, whether an abnormal RPE may influence neural crest-derived pigment cells, or conversely, abnormalities in neural crest-derived pigment cells may influence the RPE. Another problem not fully resolved concerns the mechanisms by which MITF deficiencies lead to microphthalmia. Granted, in microphthalmic Mitf-mutant mice, the RPE is abnormal and hyperproliferates and the optic fissure does not close, but is this an RPE cell-autonomous problem or does it also involve the periocular mesenchyme, which in part is contributed by the cranial neural crest and is required for normal eye morphogenesis (Akula et al., 2019; Lupo et al., 2011)? This periocular mesenchyme provides essential signals for the patterning of ectodermal ocular primordia, regulates the induction of the RPE, the lacrimal glands, the optic stalk (Fuhrmann et al., 2000; Gage et al., 2005; Kao et al., 2013), and later the eye lids (Le Lièvre and Le Douarin, 1975; Williams and Bohnsack, 2015). We do not know at present whether in Mitf mutants, the periocular mesenchyme is affected, be it directly or indirectly through the effects on melanocytes. Nevertheless, any effect of melanocytes may be subtle based on the analysis of the above mentioned Mitfmi-bw mice with their seemingly normal RPE and total lack of neural crest-derived melanocytes. In sum, MITF plays crucial roles in many functions of the RPE that are critical for the integrity and function of retinal photoreceptors. It is clear that Mitf mutations affect the RPE that in turn affects the retina but it is not known whether MITF is directly involved in the major forms of human adult onset retinal degenerations due to primary RPE deficiencies. Nevertheless, current research primarily in animal models points to a number of MITF target genes whose products in abnormal form or level are part of the pathogenic processes leading to retinal degeneration. Hence, MITF itself or the products of its regulated genes may in the future become important factors in the therapeutic arsenal aimed at preventing, delaying or even curing retinal degenerations. Even if this hope might not materialize, then the study of the roles of MITF in the RPE will still be crucial for a deeper understanding of the myriad functions this fascinating tissue has for our vision.

6.3. Antioxidant functions The role of oxidative stress in the retina is well established and antioxidant agents such as vitamin A, docosahexaenoic acid (DHA), and lutein are beneficial to retinitis pigmentosa patients (Dias et al., 2018). An alternative approach to applying exogenous agents would be to stimulate the endogenous anti-oxidant program as provided, for instance, by the MITF-regulated genes NRF2 and PGC1α described above and as reported by Xiong and collaborators (Xiong et al., 2015). These authors used adeno-associated virus (AAV) vectors in mice exhibiting acute or slow retinal degeneration to deliver NRF2 and/or PGC1α. Interestingly, they found that overexpression of NRF2 in the diseased retina, where its levels are low, had clear neuroprotective effects not only on photoreceptors but also on retinal ganglion cells while overexpression of PGC1α (that is, expression beyond the levels already seen in these neurodegenerative retinae) unexpectedly accelerated photoreceptor death. Hence, PGC1α levels should not exceed a threshold level in the retina. It is conceivable, however, that expression of PGC1α specifically in the RPE might show more protective and less adverse effects. 6.4. 9-cis-retinal and the visual cycle 9-cis-retinal is an analog of 11-cis retinal that can improve the visual performance in Rpe65−/− dogs, whose visual cycle is impaired (Gearhart et al., 2010). 9-cis-retinal also slightly slowed the development of retinal degeneration in Mitf−/− mutant mice (Wen et al., 2016). Interestingly, a pharmacological chaperone of rod photoreceptor opsin, YC-001, which can bind bovine rod opsin with an EC50 (concentration for 50% of maximal effect) similar to that of 9-cis-retinal, was able to protect Abca4−/−; Rdh8−/− mice from bright light-induced retinal degeneration (Chen et al., 2018). Furthermore, it has been shown that selective inhibition of the enzymatic activity of RPE65 protects the retina from light-induced degeneration (Shin et al., 2018), suggesting that the visual cycle may also cause toxic byproducts besides its required role in vision and that therefore a correct balance has to be maintained between beneficial and detrimental effects. In sum, then, current attempts at preventive or therapeutic interventions in photoreceptor degeneration focus on pathways regulated in the RPE by MITF. If the pathogenesis of retinal degeneration indeed involved transient or long-lasting deficiencies in MITF, then delivering MITF may be an alternative to the use of individual factors. MITF would have the added benefit of reducing cell proliferation, rather than promoting it as other factors might. The challenge, however, is how to deliver MITF efficiently and specifically to the RPE, in particular the damaged RPE. In any event, a transgenic approach to express MITF in the RPE of Mitf null mutant mice has recently been shown to partially rescue pigmentation, though not photoreception (Michael et al., 2018). 7. Challenges and future perspectives Although the above mentioned pathways hint at mechanisms by which deficiencies in MITF might cause retinal degeneration, we still know far too little about such mechanisms as their elucidation is hampered for several reasons. First, the sheer multitude of cellular functions regulated by MITF makes it difficult to provide a clear picture of hierarchies and relative importance of the various functions particularly in vivo (a problem also faced by dermatologists trying to understand the function of MITF in melanoma pathogenesis and progression). Second, the paucity of authentic adult RPE cells available for analysis precludes easy biochemical approaches. Third, adult RPE cells in monolayer culture tend to rapidly lose their differentiated state and undergo EMT and so impede analysis of homogeneous cell populations. These latter problems can be partially addressed using ES- or iPSC-derived RPE cells, which under ideal conditions can be expanded to large numbers and kept in a monolayer state that may reflect authentic RPE

Author statement Xiaoyin Ma has made 30% contribution in the preparation of this manuscript. Huirong Li has made 9% contribution in the preparation of this manuscript. Yu Chen has made 7% contribution in the preparation of this manuscript. Juan Yang has made 5% contribution in the preparation of this manuscript. Huaicheng Chen has made 4% contribution in the preparation of this manuscript. Heinz Arnheiter has made 15% contribution in the preparation of 12

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this manuscript. Ling Hou has made 30% contribution in the preparation of this manuscript.

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Acknowledgements We would like to thank Dr. Brian P. Brooks (NIH/NEI) for generous contributions to the images and Dr. Kapil Bharti (NIH/NEI) for critical reading of the manuscript. We would also like to thank all of the current and past team members for their research contributions to our projects. Our current research is supported in part by the National Natural Science Foundation of China (81870664, 81600748, 81570892, 81770946 and 81800838), the National Basic Research Program (973 Program, 2009CB526502), Natural Science Foundation of Zhejiang Province (LY18H120007), the Research Grant of Wenzhou Medical University (QTJ08006) and Research Grant of Wenzhou Medical University Eye Hospital (KYQD151211, YNZD201605, YNCX3201902). This study was also supported by the Project of State Key Laboratory of Ophthalmology, Optometry and Visual Science, Wenzhou Medical University (437201804G). Past research was supported by the intramural programs of the National Institutes of Health, United States. We apologize for any omissions due to space limitations. There is no conflict of interest among the authors. Appendix A. Supplementary data Supplementary data to this article can be found online at https:// doi.org/10.1016/j.preteyeres.2019.06.002. References Adini, I., Ghosh, K., Adini, A., Chi, Z.L., Yoshimura, T., Benny, O., Connor, K.M., Rogers, M.S., Bazinet, L., Birsner, A.E., Bielenberg, D.R., D'Amato, R.J., 2014. Melanocytesecreted fibromodulin promotes an angiogenic microenvironment. J. Clin. Investig. 124, 425–436. Akeo, K., Hiramitsu, T., Yorifuji, H., Okisaka, S., 2002. Membranes of retinal pigment epithelial cells in vitro are damaged in the phagocytotic process of the photoreceptor outer segment discs peroxidized by ferrous ions. Pigm. Cell Res. 15, 341–347. Akula, M., Park, J.W., West-Mays, J.A., 2019. Relationship between neural crest cell specification and rare ocular diseases. J. Neurosci. Res. 97, 7–15. Arnheiter, H., Hou, L., Nguyen, M.T., Bismuth, K., Csermely, T., Murakami, H., Bharti, K., 2005. Mitf-a matter of life and death for the developing melanocytes. In: Hearing, V.J., Leong, S.P. (Eds.), Melanocytes and Melanomas: the Progression to Malignancy. Humana Press, Totowa, NJ, pp. 27–49. Arnheiter, H., 2010. The discovery of the microphthalmia locus and its gene, Mitf. Pigment Cell Melanoma Res 23, 729–735. Barnstable, C.J., Tombran-Tink, J., 2004. Neuroprotective and antiangiogenic actions of PEDF in the eye: molecular targets and therapeutic potential. Prog. Retin. Eye Res. 23, 561–577. Bauer, G.L., Praetorius, C., Bergsteinsdóttir, K., Hallsson, J.H., Gísladóttir, B.K., Schepsky, A., Swing, D.A., O'Sullivan, T.N., Arnheiter, H., Bismuth, K., Debbache, J., Fletcher, C., Warming, S., Copeland, N.G., Jenkins, N.A., Steingrímsson, E., 2009. The role of MITF phosphorylation sites during coat color and eye development in mice analyzed by bacterial artificial chromosome transgene rescue. Genetics 183, 581–594. Bäumer, N., Marquardt, T., Stoykova, A., Spieler, D., Treichel, D., Ashery-Padan, R., Gruss, P., 2003. Retinal pigmented epithelium determination requires the redundant activities of Pax2 and Pax6. Development 130, 2903–2915. Bertolotto, C., Lesueur, F., Giuliano, S., Strub, T., de Lichy, M., Bille, K., Dessen, P., d'Hayer, B., Mohamdi, H., Remenieras, A., Maubec, E., de la Fouchardière, A., Molinié, V., Vabres, P., Dalle, S., Poulalhon, N., Martin-Denavit, T., Thomas, L., Andry-Benzaquen, P., Dupin, N., Boitier, F., Rossi, A., Perrot, J.L., Labeille, B., Robert, C., Escudier, B., Caron, O., Brugières, L., Saule, S., Gardie, B., Gad, S., Richard, S., Couturier, J., Teh, B.T., Ghiorzo, P., Pastorino, L., Puig, S., Badenas, C., Olsson, H., Ingvar, C., Rouleau, E., Lidereau, R., Bahadoran, P., Vielh, P., Corda, E., Blanché, H., Zelenika, D., Galan, P., French Familial Melanoma Study Group,Aubin, F., Bachollet, B., Becuwe, C., Berthet, P., Bignon, Y.J., Bonadona, V., Bonafe, J.L., Bonnet-Dupeyron, M.N., Cambazard, F., Chevrant-Breton, J., Coupier, I., Dalac, S., Demange, L., d'Incan, M., Dugast, C., Faivre, L., Vincent-Fétita, L., Gauthier-Villars, M., Gilbert, B., Grange, F., Grob, J.J., Humbert, P., Janin, N., Joly, P., Kerob, D., Lasset, C., Leroux, D., Levang, J., Limacher, J.M., Livideanu, C., Longy, M., Lortholary, A., Stoppa-Lyonnet, D., Mansard, S., Mansuy, L., Marrou, K., Matéus, C., Maugard, C., Meyer, N., Nogues, C., Souteyrand, P., Venat-Bouvet, L., Zattara, H., Chaudru, V., Lenoir, G.M., Lathrop, M., Davidson, I., Avril, M.F., Demenais, F., Ballotti, R., Bressac-de Paillerets, B., 2011. A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma. Nature 480, 94–98. Bharti, K., Gasper, M., Ou, J., Brucato, M., Clore-Gronenborn, K., Pickel, J., Arnheiter, H.,

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