Conservation in the involvement of heterochronic genes and hormones during developmental transitions

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Review article

Conservation in the involvement of heterochronic genes and hormones during developmental transitions Fernando Faunes n, Juan Larraín n Center for Aging and Regeneration, Millennium Nucleus in Regenerative Biology, Faculty of Biological Sciences, P. Universidad Católica de Chile, Alameda 340, Santiago, Chile

art ic l e i nf o

a b s t r a c t

Article history: Received 28 January 2016 Received in revised form 3 June 2016 Accepted 9 June 2016

Developmental transitions include molting in some invertebrates and the metamorphosis of insects and amphibians. While the study of Caenorhabditis elegans larval transitions was crucial to determine the genetic control of these transitions, Drosophila melanogaster and Xenopus laevis have been classic models to study the role of hormones in metamorphosis. Here we review how heterochronic genes (lin-4, let-7, lin-28, lin-41), hormones (dafachronic acid, ecdysone, thyroid hormone) and the environment regulate developmental transitions. Recent evidence suggests that some heterochronic genes also regulate transitions in higher organisms that they are controlled by hormones involved in metamorphosis. We also discuss evidence demonstrating that heterochronic genes and hormones regulate the proliferation and differentiation of embryonic and neural stem cells. We propose the hypothesis that developmental transitions are regulated by an evolutionary conserved mechanism in which heterochronic genes and hormones interact to control stem/progenitor cells proliferation, cell cycle exit, quiescence and differentiation and determine the proper timing of developmental transitions. Finally, we discuss the relevance of these studies to understand post-embryonic development, puberty and regeneration in humans. & 2016 Elsevier Inc. All rights reserved.

Keywords: Developmental transitions Metamorphosis Stem and progenitor cells Heterochronic genes Lin-28 Thyroid hormone Drosophila C. elegans Xenopus

1. Introduction Animal development involves a tight coordination between spatial and temporal patterning. Compared to spatial patterning, less is known about the factors controlling developmental timing and how developmental transitions are regulated. Examples of developmental transitions include molting (shedding of their cuticle) of worm larvae; metamorphosis of several insects including flies, butterflies, moths and bugs, frog tadpoles and the pre- to post-natal transition and puberty in mammals. All these developmental transitions involve changes at cellular, physiological and morphological levels. Developmental transitions are regulated by cellular and genetic programs that must be coordinated with changes in circulating hormones and also with environmental signals to provide a robust response to changing conditions. Different model organisms have been essential to understand the mechanisms underlying developmental transitions (Thummel, 2001). The nematode Caenorhabditis elegans (C. elegans) allowed the identification of several genes -named heterochronic genescontrolling the timing of proliferation and differentiation of n

Corresponding authors. E-mail addresses: [email protected] (F. Faunes), [email protected] (J. Larraín).

progenitor cells during larval transitions. On the other hand, the fly Drosophila melanogaster (D. melanogaster) and the frog Xenopus have been used for several decades as models to study hormonetriggered metamorphosis. Recent works in Drosophila and C. elegans provide insights on how environmental signals are interpreted and coordinated with genetic programs and the physiological status of organisms to provide a robust developmental progress. Here we review the genetic, hormonal and environmental mechanisms that regulate developmental transitions in invertebrates (C. elegans, D. melanogaster) and vertebrates (Xenopus laevis). The evidence indicates that modulation of stem and progenitor cells of larvae is a common strategy involved in developmental transitions. We also highlight that most of the genetic and hormonal mechanisms involved in developmental transitions also regulate embryonic and neural stem cells, suggesting that the study of developmental transitions should be a fertile ground for understanding stem cell biology.

2. Genetic control of developmental transitions Genetic control of developmental transitions was demonstrated by analyzing worm mutants that skip or repeat division

http://dx.doi.org/10.1016/j.ydbio.2016.06.013 0012-1606/& 2016 Elsevier Inc. All rights reserved.

Please cite this article as: Faunes, F., Larraín, J., Conservation in the involvement of heterochronic genes and hormones during developmental transitions. Dev. Biol. (2016), http://dx.doi.org/10.1016/j.ydbio.2016.06.013i

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Fig. 1. Molting in the nematode C. elegans. a) Images of C. elegans larval stages L1, L2, L3 and L4. Under unfavorable environmental conditions, larvae can undergo L1 arrest or dauer diapause. b) Expression of some heterochronic genes during larval development. c) A simplified network of interactions among environment, hormones and heterochronic genes. Food induces insulin signaling which is necessary to activate larval development at L1. In addition, food results in the synthesis of dafachronic acid (DA), which binds to the nuclear receptor DAF-12 to activate the expression of members of the let-7 miRNA family to allow development and block the dauer diapause. See text for details and references.

patterns in some tissues. Several members of this gene network have been identified in all animals and, significantly, they are involved in controlling the proliferation and differentiation of stem and progenitor cells. In this section, we discuss recent evidence about the expression and role of heterochronic genes in regulating developmental timing in invertebrates and vertebrates. 2.1. C. elegans After embryogenesis, C. elegans develops through four larval stages (L1–L4) before reaching sexual maturity (switch from L4-toadult) (Fig. 1a). Environmental conditions regulate these transitions and determine the entry into L1 arrest, into dauer state, or the progress of development. These developmental transitions involve coordinated changes in several tissues, including the intestine, the somatic gonad and the hypodermis. The newly hatched larva (L1) contains several stem and progenitor cells, including ectodermal V, H, Q and P cells, and mesodermal M cell. These progenitors divide in an essentially invariant pattern and the lineage of each progenitor cell is known with detail (Sulston and Horvitz, 1977). Developmental transitions are easily detectable in the hypodermis because a new cuticle is synthesized and molted at each stage. The hypodermis contains lateral hypodermal cells (V cells) that are tissue-specific stem cells: the so-called “seam cells”. Analysis of mutants with precocious or retarded development in

the hypodermis (detected as skipped or repeated cell division patterns compared to the wild-type) has been a successful experimental approach to study genetic programs involved in controlling developmental transitions (Ambros and Horvitz, 1984; Chalfie et al., 1981; Horvitz and Sulston, 1980; Sulston and Horvitz, 1981). These analyses, together with expression studies, established a gene network that controls larval transitions in C. elegans (Fig. 1b and c) (Ambros, 1989; Reinhart et al., 2000). In this genetic network, Lin-28 plays a central role. Lin-28 is an RNA binding protein that regulates the translation of several mRNAs, specifically blocks the biogenesis of the let-7 miRNA and regulates transcription through modulation of DNA methylation (Graf et al., 2013; Heo et al., 2008; Jin et al., 2011; Piskounova et al., 2011; Polesskaya et al., 2007; Xu et al., 2009; Zeng et al., 2015). Lin-28 is expressed in the hypodermis, muscle and neurons, and its levels decrease during the L2 stage (Moss et al., 1997) (Fig. 1b). In lin-28 loss-of-function mutants, seam cells skip the division pattern that normally occurs at the L2 stage, and the larval-toadult switch occurs earlier compared to wild-type animals (Ambros and Horvitz, 1984). Consistent with this phenotype, gain-offunction mutants repeat the L2-pattern and the larval-to-adult switch is delayed (Moss et al., 1997). One of the landmark results of these genetic screenings was the discovery of micro-RNAs (miRNAs) (Lee et al., 1993; Wightman et al., 1993). In C elegans, miRNAs lin-4 and let-7 are key players in regulating developmental transitions (Lee et al., 1993; Reinhart

Please cite this article as: Faunes, F., Larraín, J., Conservation in the involvement of heterochronic genes and hormones during developmental transitions. Dev. Biol. (2016), http://dx.doi.org/10.1016/j.ydbio.2016.06.013i

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et al., 2000; Wightman et al., 1993). lin-4 expression increases during L1 stage, allowing transition to L2 stage (Feinbaum and Ambros, 1999) (Fig. 1b). In lin-4 loss-of-function mutants L1-specific developmental events are reiterated at later larval stages. Similarly, the expression of members of the let-7 miRNA family -miR-48, miR-84, miR-241 increases during L2 stage (Abbott et al., 2005) and let-7 increases during L3-L4 stages (Reinhart et al., 2000) (Fig. 1b). Consistent with this expression pattern, let-7 lossof-function mutants repeat larval events and delay the transition to adult. lin-4 and let-7 family members regulate several targets, including Lin-28, the transcription factor Lin-14 and the E3 ubiquitin ligase Lin-41 (Feinbaum and Ambros, 1999; Slack et al., 2000) (Fig. 1c). The lin-14 loss-of-function mutant performs L2 events precociously while gain-of function mutants reiterate L1 events at later stages (Ambros and Horvitz, 1984, 1987). Lin-41 belongs to the family of proteins containing a tripartite domain composed by a RING domain, one or two B-box motifs and a coiled-coil region

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(TRIM/RBCC protein). Lin-41 is expressed in neurons, muscle and pharyngeal cells. In hypodermal seam cells, its expression decreases during L4 stage due to the expression of the miRNA let-7 (Fig. 1b and c). Gain- and loss- of function experiments showed that lin-41 negatively regulates the expression of adult genes at larval stages. In summary, studies in C. elegans unveiled a gene network comprised by a set of heterochronic genes that regulates the timing and progress of developmental transitions. This network includes miRNAs that regulate the levels of Lin-14, Lin-28 and Lin41, among others (Fig. 1c). More importantly, this program modulates larval transitions by controlling seam cell division and differentiation, thereby demonstrating a key role for stem cells in developmental transitions. 2.2. Insects Larval

transitions

and

metamorphosis

in

Drosophila

Fig. 2. Metamorphosis in Drosophila melanogaster. a) Images of larval instars and metamorphosis of Drosophila (pre-pupa to adult). b) Levels of ecdysone (blue) and some of the genes discussed in the text. Chinmo (pink) and Abrupt (dark blue) are transcription factors down-regulated by let-7 during metamorphosis and this regulation is crucial for the proper timing of cell cycle exit and differentiation of progenitor cells. miR-125 (yellow) is the orthologue of lin-4, which is transcribed with let-7 from the same locus, let-7-C locus. c) A simplified view of the main players controlling metamorphosis and stem and progenitor cells in Drosophila. The presence of food at hatching triggers the activation of insulin signaling which results in the re-activation of neuroblasts in the nervous system. Under normal conditions, when critical size is attained during the third larval instar, the release of ecdysone is induced; this regulates the cell cycle exit and differentiation of progenitor cells, in some of them by controlling the expression of the miRNA let-7. See text for details and references.

Please cite this article as: Faunes, F., Larraín, J., Conservation in the involvement of heterochronic genes and hormones during developmental transitions. Dev. Biol. (2016), http://dx.doi.org/10.1016/j.ydbio.2016.06.013i

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melanogaster (Fig. 2a) have been extensively studied, focusing mainly on control by hormones such as the juvenile hormone and ecdysone (see Section 3.2). Here, we discuss the expression and function of heterochronic genes including let-7, miR-125 (the orthologue of lin-4), lin-28 and lin-41 during the metamorphosis of Drosophila and other insects. Northern blot analysis of Drosophila showed that let-7 increases from the late third instar larvae to adult with a peak at pupa, with a similar pattern to ecdysone levels (Bashirullah et al., 2003; Pasquinelli et al., 2000; Sempere et al., 2002) (Fig. 2b). let-7, miR125 and miR-100 are expressed as a single transcript from the let7-Complex (let-7
C) locus (Caygill and Johnston, 2008; Sokol et al., 2008). Consistently, the levels of miR-125 also increase during metamorphosis (Bashirullah et al., 2003) (Fig. 2b). Most of let-7
C knock-out animals are unable to properly eclose and those that do eclose have several defects, including reduced longevity, sterility and locomotion problems. Interestingly, the timing of pupation and the external morphology of pupa and adults are normal. This indicates that these miRNAs are only required to remodel internal tissues that control adult behavior. It is unknown whether other miRNAs rescue pupation to occur at normal time or if this process is completely independent of let-7/miR-125/miR-100. The role of let-7
C miRNAs and their targets have been studied in some detail in the central nervous system (CNS) and in neuromusculature junction (NMJ). Expression from the let-7
C locus is detected in the CNS from the third instar larva to the adult (Kucherenko et al., 2012; Wu et al., 2012). The role of let-7
C has been studied during differentiation of neuroblasts of the Mushroom Body (MB). Neuroblasts (NB/NSC) are the stem and progenitor cells responsible for CNS formation and remodeling through embryogenesis and metamorphosis. The Mushroom Body is a brain center responsible for olfactory learning and memory. MB neuron subtypes γ, α′/β′, pioneer α/β and α/β neurons are established in a birth order-dependent fashion from the same progenitor during development and metamorphosis (Zhu et al., 2006). γ-neurons are born during larval stages, α′/β′ during the larval-to-pupa transition and α/β neurons during the final metamorphosis from pupa to adults. let-7
C mutants showed a high proportion of α′/β′ neurons at the expense of α/β neurons, indicating that these miRNAs are required for proper metamorphosis of the CNS. Expression of higher levels of the BTB-zinc finger transcription factors Chinmo (Chronologically inappropriate morphogenesis) and Abrupt are responsible for this defect. Expression analysis and rescue experiments demonstrate that Chinmo and Abrupt levels are regulated by let-7 and miR-125 during metamorphosis (Fig. 2(b)). Down-regulation of Chinmo and Abruptare required to form α/β neurons (Kucherenko et al., 2012; Wu et al., 2012). Although let-7
C mutants initiate thoracic and abdominal muscle contractions for eclosion, those contractions are not productive and most of the mutants are unable to properly eclose (Caygill and Johnston, 2008; Sokol et al., 2008). let-7
C mutants have a lower number of synaptic buttons at later stages of metamorphosis (Caygill and Johnston, 2008) and present immature properties (Sokol et al., 2008). let-7, miR-125 and miR-100 single mutants showed that let-7 is necessary for NMJ maturation (Sokol et al., 2008). In wild-type animals, Abrupt is expressed in myoblasts (muscle progenitors) during metamorphosis and downregulated prior to eclosion. In contrast, Abrupt is not down-regulated after eclosion in let-7
C mutants (Caygill and Johnston, 2008). This persistent expression of Abrupt is responsible for the low number of synaptic buttons during maturation. In addition to their role in MB neurogenesis and NMJ maturation, the miRNA let-7 is required to stop proliferation of wing cells during metamorphosis (Caygill and Johnston, 2008), similar to the role in C. elegans hypodermal cells (Reinhart et al., 2000). In wing

cells, Abrupt is also a target of let-7. However, down-regulation of Abrupt in let-7
C mutants does not rescue all the defects of let7
C mutants, indicating that other specific targets are downregulated by let-7, miR-125 or miR-100 in other tissues. In short, the loss of these miRNAs induces specific defects in eclosion, the timing of proliferation (wing cells), differentiation of NB/NSC and maturation of NMJ (muscles) during Drosophila metamorphosis. This heterochrony is probably the reason for defects in adult let7
C mutants and shows that the regulation of proliferation and differentiation of progenitor cells during metamorphosis is crucial for normal development. Significantly, the expression and the possible role of let-7 on metamorphosis has also been studied in silkworms Bombyx mori (Ling et al., 2014; Liu et al., 2007) and in cockroaches Blatella germanica (Rubio and Belles, 2013). In contrast to let-7, less is known about the role of other heterochronic genes during insect metamorphosis. Lin-14 is thought to be specific to nematodes and no orthologue has been found in other animals. Lin-28 is involved in Drosophila oogenesis (Stratoulias et al., 2014). Its protein levels decrease from embryogenesis to larval stages and then increase during metamorphosis but they are not detected in whole extracts of adult flies (Moss and Tang, 2003). In the adult intestine, Lin-28 is important for food-triggered proliferation of stem cells through regulation of insulin signaling (Chen et al., 2015). It is not known if Lin-28 is expressed in specific tissues or in proliferative cells or if it is regulated by ecdysone during larval development. Further work is needed to determine how conserved is the role of Lin-28 and other heterochronic genes during transitions and metamorphosis in insects. 2.3. Vertebrates Several members of the heterochronic gene network identified in C. elegans are highly conserved in vertebrates. Interestingly, some have been involved in the control of self-renewal and differentiation of stem/progenitor cells, including embryonic stem cells (ESC). We review the expression and role of Lin-28, Lin-41 and the miRNAs let-7 and miR-125 on stem/progenitor cells and propose its potential role on vertebrate developmental transitions. 2.3.1. Non-mammalian species: Xenopus, zebrafish and flounder Xenopus laevis development is divided into embryogenesis (from fertilization to Nieuwkoop Faber (NF) stage 21), tailbud and tadpole development (from NF stage 22 to NF stage 45) and metamorphosis that ends with a juvenile organism (from NF stage 46 to NF stage 66, Fig. 3a). Metamorphosis is divided into three major phases: i) pre-metamorphosis (NF stage 46–54), starting with the development of the thyroid gland until thyroid hormones are detected in plasma, ii) pro-metamorphosis (NF stage 54–58): when thyroid hormones levels start to increase and iii) climax of metamorphosis (NF stage 59–66): from the end of pro-metamorphosis until resolution and tail reabsorption (NF stage 66) (Fig. 3a and b) (Brown and Cai, 2007; Moreno et al., 2014). In this section we focus on the expression and possible role of heterochronic genes on transitions and compare the expression of these genes to levels of thyroid hormones during development. The role of thyroid hormones and their potential interaction with heterochronic genes is discussed in Section 3.5. Lin-28 is highly conserved in animals and two paralogues have been identified in vertebrates, lin-28a and lin-28b. They are expressed at early developmental stages in zebrafish (Ouchi et al., 2014), Xenopus (Faas et al., 2013; Moss and Tang, 2003) and mice (Moss and Tang, 2003; Yang and Moss, 2003). In Xenopus, Lin-28 morphant embryos show mesoderm defects at early stages (Faas et al., 2013). However, the expression and function of Lin-28 during Xenopus late larval development and metamorphosis has not been characterized.

Please cite this article as: Faunes, F., Larraín, J., Conservation in the involvement of heterochronic genes and hormones during developmental transitions. Dev. Biol. (2016), http://dx.doi.org/10.1016/j.ydbio.2016.06.013i

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Fig. 3. Metamorphosis in Xenopus laevis. a) Images of different stages of Xenopus laevis according to Nieuwkoop-Faber (NF stages) from stage 46 when the thyroid gland starts to develop to stage 66 when metamorphosis is complete. This process is divided into three phases according to the levels of thyroid hormones. b) Levels of thyroid hormones thyroxine (T4, blue) and triiodothyronine (T3, green) during metamorphosis. From stage 46 to stage 54 no thyroid hormones are detected in the plasma (premetamorphosis). This phase is characterized by body growth and hindlimb development. Pro-metamorphosis starts when TH are detected from stage 54. At the climax of metamorphosis, forelimbs emerge and the remodeling of the intestine and reabsorption of the tail begins. c) Hormonal axis involved in the control of X. laevis metamorphosis. Environmental conditions are sensed by the hypothalamus which secretes Corticotropin-Releasing Factor (CRF) and Thyrotropin-Releasing Hormone (TRH) to stimulate the pituitary gland to secrete Adrenocorticotropic hormone (ACTH) and Thyroid-stimulating hormone (TSH), respectively. ACTH stimulates the adrenal gland to secrete glucocorticoids (GC) and TSH stimulates the thyroid gland to secrete T4 and a lower amount of T3. Target tissues convert T4 to T3 and synergize with GCs to respond during metamorphosis.

In zebrafish, lin-28a is expressed during early embryogenesis, from fertilization to 12 h post-fertilization (hpf) and lin-28b is detected from 4 hpf to 24 hpf (Ouchi et al., 2014). Knock-down of lin-28, using morpholinos, decreases BrdU incorporation early in embryogenesis, indicating that Lin-28 is required for proliferation in the embryo, consistent with the role of Lin-28 in the control of progenitor cells. Lin-28 knock-down results in higher levels of let-7 and lower levels of lin-41. Interestingly, knock-down of lin-28 decreases the levels of miR-430a/b, which are known for their involvement in the clearance of maternal transcripts and the maternal-to-zygotic transition (Giraldez et al., 2006). Expression of lin-28 genes has not been studied at later stages. In vertebrates, the let-7 family consists of several members having a conserved 5´seed sequence and variable 3´sequences (Roush and Slack, 2008). Expression of some members of the let-7 family has been studied during early Xenopus development (Faas et al., 2013). Expression analysis of Xenopus tropicalis tadpole

extracts by cDNA libraries identified several miRNAs expressed during metamorphosis, including some members of the let-7 and miR-125 families (Hikosaka et al., 2007). Northern blot analysis showed that let-7 increases slightly at the climax of metamorphosis (stage 64) compared to pro-metamorphosis (Hikosaka et al., 2007). However, a detailed analysis of isoforms or their spatial expression in different tissues during development has not been performed. Similarly, in Japanese flounder Paralichthys olivaceus, let-7 isoforms are expressed during metamorphosis with a peak at pro-metamorphosis and climax stages when the levels of circulating thyroid hormones are higher (de Jesus et al., 1991; Fu et al., 2013). let-7 and miR-125 increase at the embryo to larval transition in zebrafish (Ouchi et al., 2014). Interestingly in all these cases, higher levels of these miRNAs are detected at metamorphosis in Xenopus and flounder and in the embryo to larval transition in zebrafish (Brown and Cai, 2007; de Jesus et al., 1991; Liu and Chan, 2002), suggesting that they could be regulated by

Please cite this article as: Faunes, F., Larraín, J., Conservation in the involvement of heterochronic genes and hormones during developmental transitions. Dev. Biol. (2016), http://dx.doi.org/10.1016/j.ydbio.2016.06.013i

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Fig. 4. Heterochronic genes regulate stem cell renewal and differentiation in mammals. Lin-28, Lin-41 and the miRNAs let-7 and miR-125 are highly conserved in mammals. Lin-28 and Lin-41 promote self-renewal and they are expressed in stem and progenitor cells in vitro and in vivo in several tissues during development, including the retina, the cochlea and the brain cortex. In contrast, let-7 and miR-125 are expressed in differentiated cells.

thyroid hormones and involved in regulating these developmental transitions (Section 3.5). 2.3.2. Embryonic stem cells, progenitor cells and mammalian development lin-28 is expressed in embryonic stem cells (ESCs) and several cancer cell lines (Alajez et al., 2012; Molenaar et al., 2012; Moss and Tang, 2003; Zhu et al., 2010). Its expression decreases with ESC differentiation (Fig. 4) and increases the efficiency of cell reprogramming and production of induced pluripotent stem cells (iPSC) (Yu et al., 2007). lin
28 blocks the processing of pri-let-7 in ESCs (Viswanathan et al., 2008) and also regulates the translation of several genes, including those involved in cell cycle regulation and glucose metabolism (Graf et al., 2013; Polesskaya et al., 2007; Xu et al., 2009). Therefore, lin
28 is a master regulator of ESC selfrenewal and it targets genes in stem and progenitor cells have been reviewed (Shyh-Chang and Daley, 2013; Thornton and Gregory, 2012). lin
28 is also expressed during early neural development and in neural stem and progenitor cells (NSPCs) (Balzer et al., 2010; Yokoyama et al., 2008). In vitro studies indicate that constitutive expression of Lin-28 - in P19 embryonic carcinoma cells blocks retinoic acid-induced gliogenesis but does not affect neurogenesis (Balzer et al., 2010), suggesting that a decrease of Lin-28 is required for the neuron-to-glia switch. Interestingly, in a model of neurogenesis using human embryonic stem cell-derived neural progenitor cells, Sox2 increases Lin-28 expression by binding to a proximal site in the promoter and regulating acetylation (Cimadamore et al., 2013). In this experimental model, inducible overexpression of Lin-28 rescues the defects on cell proliferation and early phases of neurogenesis in the absence of Sox2, indicating that Lin-28 is an important factor downstream of Sox2 in NSPCs. In contrast to Lin-28, miRNAs let-7 and miR-125 increase during ESC differentiation (Fig. 4). Their expression increases at later stages in mice development (E14 to P0) and overexpression of these miRNAs accelerates retinal development (La Torre et al., 2013). let-7 is expressed in developing CNS, in the limb primordia and brachial arches (Wulczyn et al., 2007). Regulation by let-7 and miR125 is important for neural stem cell maintenance and differentiation (Patterson et al., 2014; Rybak et al., 2008; Wulczyn et al., 2007; Zhao et al., 2009). Recently, it has been shown that let-7 and miR-125 are also required for astrocyte differentiation of glial progenitor cells in vitro (Shenoy et al., 2015). The role of Dicer and miRNAs have been shown in retinal neurogenesis (Decembrini et al., 2009; Georgi and Reh, 2010; La Torre et al., 2013).

Overexpression of let-7 results in a premature cell cycle exit, consistent with a role of the Lin-28/let-7 axis in the control of proliferation and differentiation of neural progenitor cells. Lin-41 (also known as TRIM71) is also highly conserved in vertebrates (Lancman et al., 2005). Lin-41 is a stem cell E3-ubiquitin ligase for the miRNA pathway protein Ago2 and therefore modulates miRNA-mediated repression (Rybak et al., 2009). Lin-41 represses translation of several genes in mouse embryonic stem cells (Loedige et al., 2013) and promotes cell proliferation (Chang et al., 2012a), and reprogramming of somatic cells in mammals (Worringer et al., 2014). During mouse development, lin-41 is expressed before E14.5 mainly in limbs, brachial arches, eyespot and the developing brain (Schulman et al., 2005). Lin-41 is required for neural tube growth and closure and is essential for mouse development (Cuevas et al., 2015; Chen et al., 2012; Maller Schulman et al., 2008). Lin-41 mutant embryos show reduced cell proliferation in the epithelium and premature differentiation of neurons (Chen et al., 2012). After birth, Lin-41 is specifically expressed in ependymal brain cells (Cuevas et al., 2015). Therefore, Lin-41 favors cell proliferation of stem and progenitor cells in vitro and during early development by controlling several gene levels. In summary, key factors of developmental transitions in C. elegans (Lin-28, Lin-41, let-7 and miR-125) are highly conserved in mammals and play a role in the control of stem and progenitor cells (Fig. 4). Altogether, the expression pattern and the role of these heterochronic genes during differentiation in mammal stem cells and mouse development are very similar to the function of these genes on stem and progenitor cells during C. elegans larval transitions. In future, probably more genes of the C. elegans heterochronic network will be identified and studied in mammal stem cells and development. 2.3.3. Puberty and growth Although a metamorphosis with extensive morphological transformations as those seen in insects and amphibians are not visually evident in mammals, at least two clear transitions occur during its life cycle: birth and puberty. Birth and its relation to thyroid hormones are discussed in Section 3.4. The transition to sexual maturity involves relatively wellknown hormone-induced changes in anatomy and behavior. In contrast, only few genetic determinants controlling the timing of puberty have been identified to date (Gajdos et al., 2010). Importantly, genetic variations in Lin-28 loci have been associated with timing defects at puberty in humans (Elks et al., 2010; He et al., 2009; Ong et al., 2009; Park et al., 2012; Perry et al., 2009; Sulem et al., 2009; Tommiska et al., 2010; Zhu et al., 2010). In rats, Lin-28 levels decrease in the hypothalamus from birth to puberty (Sangiao-Alvarellos et al., 2013). In mice, the vaginal opening is a marker for the onset of puberty and 50% of wild-type animals have reached puberty around the age of 25 days. In contrast, 50% of animals that overexpress Lin-28A reach puberty around the age of 27–28 days, showing that Lin-28A delays puberty (Zhu et al., 2010). In addition, overexpression of Lin-28A leads to increased body size (Zhu et al., 2010) and lin-28 mutant mice have growth defects (Shinoda et al., 2013). The effect in body size is due to increased number of cells rather than increased cell size. Transgenic animals with higher levels of Lin-28A show enhanced glucose utilization in peripheral tissues and increased insulin sensitivity compared to wild type animals. The role of Lin-28 on glucose metabolism and stem cell function suggest that this factor is crucial between animal growth and maturity. Future work is needed to determine which specific tissues play a role in the timing of puberty and its relation to normal growth and obesity. No other heterochronic genes have been related to puberty.

Please cite this article as: Faunes, F., Larraín, J., Conservation in the involvement of heterochronic genes and hormones during developmental transitions. Dev. Biol. (2016), http://dx.doi.org/10.1016/j.ydbio.2016.06.013i

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3. Hormonal and environmental control of developmental transitions

3.2. Role of insulin signaling and ecdysone on metamorphosis in D. melanogaster

Cellular programs must be coordinated with the organism's physiological state and external stimuli in order to provide a robust regulation of developmental transitions. Some animals can arrest, delay or accelerate developmental transitions or go into alternative diapause-like stages when experiencing harsh conditions. In the same way that C. elegans has provided fundamental insights into the genetic programs that regulate transitions, insects and amphibians have been invaluable experimental organisms to understand how hormones and the environment control metamorphosis. More recently, the role of hormones in the developmental transitions of C. elegans has been described. Hormones allow global regulation of cellular responses in different tissues, a crucial fact to coordinate physiological responses to environmental changes. Here we propose that the response to environmental signals involves regulating stem and progenitor cells that can remain quiescent, proliferate or differentiate in response to hormones. In this section, we review how environmental conditions are sensed and transformed into hormonal signals that coordinate different tissues and the response of stem/progenitor cell and how they impact on the heterochronic gene network.

Drosophila larvae increase their mass 200 fold before the formation of the puparium, the rigid outer shell covering the pupa (Fig. 2a). The sensing of nutrients, the regulation of larval growth and the timing of metamorphosis involve a complex interaction among tissues (fat body, CNS, intestine, prothoracic gland) and hormones (insulin, ecdysone) (Andersen et al., 2013) (Fig. 2c). Insulin signaling controls the growth of larvae and the activation of NB/NSC at the first larval instar. Then, activation of the ecdysone pathway triggers the progress of metamorphosis including puparation and eclosion. Here, we discuss the role of insulin and ecdysone on NB/NSC proliferation and differentiation during CNS development. Development of the CNS, including neuron and glia formation from neural progenitors, has been extensively characterized. In a first neurogenic wave, embryonic NB/NSC, generate all the cells that form the larval CNS but only 10% of these cells remain in the adult CNS. On completing embryogenesis, most NB/NSC enter into quiescence. A second wave of neurogenesis during larval and pupal stages supports the construction of the adult CNS. The reactivation of NB/NSC and cell-cycle exit during metamorphosis are crucial to generate the proper number of neurons and glia for normal function and to avoid tumor formation in the adult CNS (Homem and Knoblich, 2012). In the Drosophila CNS, the reactivation of NB/NSC proliferation during the first and second larval instars involves nutrition-dependent factors (Briton and Edgar, 1998). Briefly, dietary amino acids activate the TOR pathway in fat body cells (Colombani et al., 2003). An unidentified fat-derived signal is released to circulation and activates TOR/PI3K pathways in glial cells in the CNS. These pathways trigger Insulin-like peptides (ILPs) by glial cells that induce proliferation in NB/NC during larval stages (Chell and Brand, 2010; Sousa-Nunes et al., 2011). In low food conditions, concentration of fat body molecules decreases, leading to a low activation of IPCs and a low release of insulin that delays growth. After reaching the critical size at the third instar, synthesis of prothoracicotropic hormone (PTTH) is induced in neurosecretory cells in the brain. PTTH activates the biosynthesis of ecdysone in the prothoracic gland (PG). The PG integrates insulin signaling, Hedgehog (Hh) signaling and PTTH levels to synthetize ecdysone. A peak of ecdysone occurs at late third instar and triggers pupariation (Fig. 2b). Ecdysone is modified to 20-hydroxyecdysone (20E) by the P450 monooxygenase Shade which is expressed in the fat body, midgut, epidermis, salivary glands, Malpighian tubules and ovaries (Petryk et al., 2003). Ecdysone (we refer to ecdysone and 20E as “ecdysone” for simplicity) binds its nuclear receptor (EcR), which forms a heterodimer with Ultraspiracle protein (USP), a retinoid X receptor orthologue. This EcR/USP heterodimer interacts with several cofactors to regulate gene expression and trigger specific cellular responses (Yamanaka et al., 2013). In the CNS, two isoforms of the EcR -EcR-A and EcR-B1- are expressed during larval and pupal stages (Truman et al., 1994). In the absence of ecdysone, EcR is a transcriptional repressor, similar to DAF-12 (Section 3.1) and the thyroid hormone receptor (Section 3.3). Therefore, EcR also controls timing by avoiding precocious expression of target genes that could result in early differentiation of progenitor cells, as described in primordial germ cells in the larval ovary (Gancz et al., 2011). Different regions in the CNS present specific patterns of EcR-A and EcR-B1 expression but they correlate with specific responses to ecdysone. EcR-A is expressed in neurons during maturation at the start of metamorphosis. In contrast, EcR-B1 is expressed in progenitor cells undergoing divisions. These results indicate that specific receptor isoforms are important for cellular responses and the switch could be a strategy

3.1. Role of insulin signaling and dafachronic acid in C. elegans The availability of food can affect developmental transitions of C. elegans at different stages. Under normal circumstances, ethanol and amino acids induce the expression of insulin-like genes in the hypodermis and increase the levels of lin-4 (Fukuyama et al., 2015). This activation is required in hypodermal cells for progenitor P-neuroblasts and M-mesoblasts to exit quiescence, proliferate and promote the progress from L1 to L2 (Fig. 1c). Hatching in the absence of food induces “L1 arrest” and larva stops development at L1 (Fig. 1a). In this state, progenitor cell divisions do not occur, the heterochronic genes are not activated and larvae can survive for several weeks. miRNA miR-235 increases during starvation and is required in the hypodermis and glia for suppressing larval development (Kasuga et al., 2013). Cellular mechanisms linking nutrition to the L1 arrest are not completely clear, but Insulin/Insulin-like growth factor signaling (IIS) is a critical regulator (Baugh, 2013). IIS negatively regulates the levels of miR-235 in hypodermis and glial cells and triggers progenitor cells to exit quiescence during L1 stage (Fig. 1c). In summary, these studies begin to reveal how nutrition regulates the activation of developmental programs including the re-activation of the division of progenitor cells and show the cross-talk among different progenitor cells to coordinate response in the organism. In addition to L1 arrest, adverse conditions after L1 stage, such as limited food, high temperature and high density trigger dauer larva formation, a modified stage that allows survival for several months. This process has been extensively studied and several genes involved have been identified (Fielenbach and Antebi, 2008). Integration of environmental signals, such as dauer pheromone, nutrients and temperature, is performed by amphid neurons ASI and ASJ (Fielenbach and Antebi, 2008). These cells produce agonistic and antagonistic insulin-like peptides (ILPs) and TGF-β. Agonistic ILPs and TGF-β induce the synthesis of bile acidlike Δ
4 and Δ
7 dafachronic acids (DA) by the enzyme DAF-9/ cytochrome P450, mainly expressed in endocrine XXX cells (Motola et al., 2006; Schaedel et al., 2012) (Fig. 1c). A key player in the decision between L3 stage or dauer larva is the DA receptor DAF12, a nuclear receptor related to the vertebrate vitamin D and LXR receptors. How DAF-12 interacts with heterochronic genes to regulate development is discussed in Section 3.5.

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to exit the cell cycle. Interestingly, the EcR gene itself is a target of ecdysone (Huet et al., 1995; Karim and Thummel, 1992) and the continuous presence of ecdysone might switch the response in progenitor cells. In addition, the expression of receptors at proper times during development determines the competence window for progenitor cells to respond to hormones. Ecdysone is also required to terminate proliferation of NB/NSC during pupal stages (Homem et al., 2014). Ecdysone through EcR and the Mediator complex induces a metabolic change in NB/NSC from glycolysis to oxidative phosphorylation that results in NB/ NSC shrinkage (Homem et al., 2014). This change leads to differentiation of NB/NSC after larval-to-pupal transition and is a mechanism to ensure cell cycle exit of progenitor cells to control the formation of the CNS and avoid tumor formation. In the optic lobes, analysis of ecdysone receptor dominant-negative clones showed an increase in neuroepithelial cells and a decrease in neurons relative to controls, indicating that ecdysone signaling is required to switch from symmetric proliferation to asymmetric proliferation (Lanet et al., 2013). In summary, ecdysone receptors coordinate the timing of activation of gene programs in NB/NSC in Drosophila. 3.3. Role of thyroid hormones in metamorphosis in X. laevis Amphibian metamorphosis involves external changes such as limb development and reabsorption of the gills and tail, and also very extensive remodeling of the CNS and the intestine. Environmental conditions such as food availability, temperature and the presence of predators impact on development and the timing of metamorphosis. In general, two hormonal axes sense the environment and coordinate the timing of amphibian metamorphosis: the hypothalamus-pituitary-adrenal gland (HPA) axis and hypothalamus-pituitary-thyroid gland (HPT) axis (Fig. 3(c)). In contrast to Drosophila, the role of Insulin signaling on amphibian metamorphosis has not been studied. Levels of insulin mRNA decrease at the climax of metamorphosis and then increase again at the end of metamorphosis, consistent with the remodeling of the pancreas (Mukhi et al., 2009). Interestingly, in Rana clamitians, the removal of the pancreas before metamorphosis has only a minor effect on glucose levels (Frye, 1964), suggesting a minor role on the control of metabolism and metamorphosis. In this review we focused mainly on the role of the HPT axis in amphibian metamorphosis. The hypothalamus regulates the function of the pituitary gland by secreting the Corticotropin-Releasing Factor (CRF) and the Thyrotropin-Releasing Hormone (TRH). Before metamorphosis, CRF stimulates secretion of Adrenocorticotropic hormone (ACTH) and Thyroid-stimulating hormone (TSH) by the pituitary gland. The adrenal gland secretes corticosteroids, including glucocorticoids (GC) cortisol and corticosterone, which synergize with thyroid hormones (TH) in target tissues to promote metamorphosis. The thyroid gland mainly secretes thyroxine (T4) and lower amounts of the more active form triiodothyronine (T3) (Brown and Cai, 2007). After metamorphosis, TRH regulates the function of the pituitary gland. TH transporters and deiodinases regulate intracellular levels of active T3 and therefore their expression is crucial for the competence of tissues to respond to the hormone (Cai and Brown, 2004; Kawahara et al., 1999; Shi et al., 1996). Type II deiodinase (D2) converts T4 to T3 and its expression is consistent with the time when tissues change during metamorphosis (Cai and Brown, 2004; Nakajima et al., 2012). For instance, the CNS expresses D2 during pre-metamorphosis when proliferation occurs (Cai and Brown, 2004) and the intestine and tail express D2 at higher levels during the climax of metamorphosis when these tissues are changing. Experiments using the D2 inhibitor iopanoic acid show

that D2 activity is required for T4-induced cell proliferation in the brain, spinal cord and limbs during Xenopus pre-metamorphosis, indicating that its expression is crucial for progenitor cell response (Cai and Brown, 2004). T3 and T4 (with lower binding affinity) control gene expression through two nuclear receptors TR-α and TR-β (Furlow and Neff, 2006). These receptors can both activate and repress gene expression, involving the recruitment of different cofactor complexes and histone modifications. TRs interact with retinoid X receptors (RXR) to form heterodimers and regulate gene expression, similar to EcRs/USP interaction in Drosophila. Chromatin immunoprecipitation assays have shown that unliganded receptors interact with repressors of transcription in the promoter of some target genes (Sachs et al., 2002), similar to EcR described above (Section 3.2). Recently, using genome editing, it has been shown that TR-α represses metamorphosis gene programs before the levels of T3 start to increase in X. tropicalis (Choi et al., 2015; Wen and Shi, 2015). Therefore, TR-α is crucial for proper timing of amphibian metamorphosis. To understand the mechanisms of T3 action in target tissues, several screenings have been done in whole brains, tails and limbs. These experiments have shown that T3 controls multiple biological processes (Kulkarni and Buchholz, 2013). These transcriptional programs are consistent with tissue response, including apoptosis and proteolysis in the tail and cell proliferation in the limbs. A limitation of these experiments is the mixture of different cell types in the tissue, but with the advance of reporter gene tools in Xenopus, similar approaches could be done in isolated populations of cells in future. The CNS undergoes extensive remodeling during amphibian metamorphosis. BrdU incorporation experiments have shown that endogenous proliferation in the brain is higher during pro-metamorphosis (Denver et al., 2009; Thuret et al., 2015). Analysis of mitotic cells in the spinal cord showed a peak of proliferation at NF stage 53 (Thors et al., 1982). These analyses showed that proliferation peaks before T3 levels peak in plasma (Brown and Cai, 2007). This suggests that CNS is highly sensitive to T3 levels, consistent with the fact that it is one of the first tissues to respond to T3 (Denver, 1998). In line with this, the first effect of T3 is to promote cell proliferation (Cai and Brown, 2004). Incubation for 2 days with high doses of exogenous T3 (50 nM) induce an increase in BrdU incorporation in the CNS compared to controls, specifically during pro-metamorphosis and not after NF stage 56– 57 (Denver et al., 2009). However, a recent study focusing on neural and progenitor Sox3 þ cells showed that incubation with a lower dose of exogenous T3 (5 nM for 1 d) induces an increase in proliferation only in the fast-cycling Sox3þ population after metamorphosis, identified with pulses of EdU and IdU (Preau et al., 2016). Although the discrepancy between these results is not understood, differences in the doses and duration of T3 treatment and in the response of specific cell populations due to differential expression of deiodinases could explain these results (Preau et al., 2016). In both cases, this T3-induced proliferation is predominantly dependent on TR-α indicating that receptor isoform is important to determine cellular response (Denver et al., 2009; Preau et al., 2016). The association of different T3 receptor isoforms with specific cellular responses is also observed in Drosophila EcR, as discussed above (Truman et al., 1994). It is not known whether this proliferation is dependent on the presence of a higher number of neural progenitor cells during pre- and pro-metamorphosis that undergo differentiation, but it is an interesting possibility. T3 also induces neurogenesis in Xenopus (Schlosser et al., 2002). Therefore, T3 is crucial to control the balance between cell proliferation and differentiation. Competence and specific response to T3 in a cell will probably depend on the levels of T3, the expression of a

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specific receptor isoform, the expression of other factors and the cross-talk with other signaling pathways (Kress et al., 2009). It is tempting to speculate that T3 could induce a change in metabolism that triggers the exit of proliferation, similar to the effect of ecdysone on neural progenitors during Drosophila metamorphosis (Homem et al., 2014). Although the role of T3 in the balance between cell proliferation and differentiation of neural progenitors is very clear, these experiments do not rule-out the possibility of intrinsic programs or heterochronic genes controlling the competence of the CNS to respond to the hormone or to activate or inhibit T3 signaling. Future work is required to analyze this possibility and to determine the effect of nutrition on the control of neural progenitor cells. In addition to the CNS, the intestine undergoes extensive remodeling during the climax of metamorphosis, decreasing 75% in

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length and forming a folded surface (Schreiber et al., 2005). Larval epithelial cells undergo apoptosis and disappear almost completely by stage 63 (Ishizuya-Oka and Ueda, 1996). Morphological and marker analysis showed that all larval epithelial cells are differentiated at pre- and pro-metamorphosis stages. Undifferentiated (progenitor) cells are first detected at stage 60 when the levels of T3 are high. These progenitor cells proliferate to form the adult intestine (Ishizuya-Oka and Ueda, 1996). Studies using recombinant organ culture with epithelial and non-epithelial tissues derived from GFP-transgenic and non-transgenic animals indicate that these progenitor intestinal stem cells originate from the larval epithelium (Ishizuya-Oka et al., 2009). The absence of undifferentiated cells prior to the climax of metamorphosis suggests that T3 induces dedifferentiation of some larval epithelial cells that proliferate to form the adult intestine. Mechanisms by

Fig. 5. Model integrating the environmental, hormonal and genetic control of developmental transitions. Environmental conditions are sensed and integrated by sensor tissues including the sensory neurons, the fat body and the hypothalamus in C. elegans, Drosophila and Xenopus, respectively (red). Sensor tissues produce hormonal signals (PTTH, ILP, CRF, TRH, ACTH, TSH) that impact endocrine glands such as XXX cells, the prothoracic gland, the adrenal gland and the thyroid gland (blue) and transform environmental signals into specific hormones released into circulation (DA, Ecdysone, GC, TH). Stem and progenitor cells respond to hormones at proper times according to their competence (expression of receptors and activating enzymes). On the other hand, genetic programs such as the heterochronic gene network control the timing of proliferation and cell-cycle exit in some progenitor cells. Stem and progenitor cells must integrate this information in order to proliferate or differentiate at specific times during development. We hypothesize that hormones and genetic networks could be linked. By connecting these programs, organisms could synchronize physiological signals with intrinsic cellular programs during developmental transitions. Prothoracic hormone (PTTH); Insulin-like peptides (ILP); Thyrotropin-Releasing Hormone (TRH); Corticotropin-Releasing Factor (CRF); Thyroid-stimulating hormone (TSH); Adrenocorticotropic hormone (ACTH); dafachronic acid (DA);glucocorticoids (GC); thyroid hormone (TH).

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which T3 induces dedifferentiation of some larval epithelial cells and not others are unknown. In summary, the regulation of amphibian metamorphosis by TH and their receptors involves mechanisms that are very similar to those involved in the control of stem and progenitor cells during invertebrate transitions, such as the synthesis of a hormone that is converted more actively in tissues (ecdysone/20E) and the presence of nuclear receptors that act as transcriptional repressors in the absence of ligands which are converted into transcriptional activators by ligand binding (DAF-12/DA, EcR/20E) (Fig. 5). Importantly, the differential expression of receptors, transporters, activating enzymes (i.e. deiodinases) will determine the timing of the response of stem and progenitor cells. The activation of the hormonal axis at physiological levels is controlled by environmental cues that are integrated mainly by the brain with inputs from other tissues. 3.4. Hormonal regulation of neurogenesis and pre- to post-natal transition in mammals As we have discussed, the physiological control of developmental transitions is crucial to coordinate the response of different tissues at proper times and hormones are key factors in this regulation. The control of self-renewal and differentiation of stem cells by hormones has been largely recognized and studied in mammals (Gancz and Gilboa, 2013). Here we focus only on TH and their effect on stem and progenitor cells during mammalian development, because this hormone is crucial for vertebrate transitions (Laudet, 2011). We discuss their role during mammalian neurogenesis because mice and rats have been excellent experimental models to understand the cellular and molecular mechanisms involved in the control of neural and progenitor cells by the thyroid hormone. This information is important to compare the presence of similar mechanisms in amphibian metamorphosis where the effect of T3 can be studied in tadpoles without the effect of maternal hormones. T3 and its receptors directly regulate the expression of several target genes in neural progenitor cells controlling the balance between proliferation and differentiation. (Durand and Raff, 2000; Kapoor et al., 2012; Puzianowska-Kuznicka et al., 2006; Stergiopoulos and Politis, 2013). For example, in adult mice, T3/TR represses sox2 expression in vivo and favors neurogenesis (LópezJuárez et al., 2012). T3/TR diminishes c-myc expression in adult neural stem cells (Lemkine et al., 2005). Consistent with these results, hypothyroidism increases proliferation in postnatal mice (Hadj-Sahraoui et al., 2000). TR-α is, in general, ubiquitously expressed and could mediate proliferation of progenitor cells in a first phase. Then, the T3/TR-αinduced expression of the TR-β gene, could trigger differentiation of progenitor cells. In line with this idea, cycling of adult NSC requires TR-α (Lemkine et al., 2005) and loss of TR-β increases proliferation in adult hippocampus (Kapoor et al., 2011). By expressing different isoforms of the receptor, stem and progenitor cells could generate different cellular responses. To characterize the specific function of each isoform it is important to determine the gene targets. Using ChIP-on-chip, several target genes of TR-β were identified in mice cerebellum at post-natal day 15 when a peak of circulating T3 is detected (Section 3.5), which is critical for cerebellum function (Dong et al., 2009). Future similar experiments in vivo will be important to determine specific targets of each receptor. The interaction of these isoforms with specific partners could allow the expression of specific target genes that change the competence to respond to the same hormone or to other extracellular signals during development. Therefore, the regulation of the levels of each isoform and how they change during development in a single progenitor cell is crucial for the

decision between proliferation and differentiation. The levels of T3 signaling are essential for perinatal development in mammals (Ahmed et al., 2008). Similar to the increase of T4 and T3 levels in plasma during amphibian metamorphosis, thyroid hormones increase around 2–3 weeks after birth in mice, rats and humans (Eastman and Zimmerman, 2009; Hadj-Sahraoui et al., 2000; Obregon et al., 1991; Polak et al., 2004; Williams et al., 2004), suggesting conserved roles of this hormone in all vertebrates (Buchholz, 2015; Laudet, 2011; Paris and Laudet, 2008). T3 receptors and enzymes involved in the control of T3 levels are conserved in animals, and several similarities in T3 action in different target organs have been identified between mammals and amphibians (Buchholz, 2015). Specifically, TH induce intestine remodeling (Sirakov and Plateroti, 2011), pancreatic β-cell maturation (Aguayo-Mazzucato et al., 2013) and profound changes in the CNS (Morvan-Dubois et al., 2013) that are crucial for the transition from intra- to extra-uterine life (Buchholz, 2015). Alteration in the levels of T3 during pre- and post-natal development result in disorders and the consequent defects in brain development have been studied for a long time (Patel et al., 2011; Williams, 2008). 3.5. Interaction between hormones and heterochronic genes For developmental transitions to proceed normally, genetic programs must be coordinated with environmental and physiological signals through hormones. In this section, we discuss recent evidence that links hormonal control of some components of the heterochronic gene network, mainly let-7. This regulation adds a new layer for the control of self-renewal and differentiation of stem and progenitor cells during developmental transitions. In C. elegans, a favorable environment induces the synthesis of DA by the endocrine XXX cells (Schaedel et al., 2012). DAF-12 bound to DA directly increases the expression of members of the let-7 family miRNA miR-84 and miR-241 and allows L2-to-L3 transition in seam cells (Bethke et al., 2009). DAF-12 is itself a target of let-7 in seam cells, forming a regulatory loop (Grosshans et al., 2005; Hammell et al., 2009). In unfavorable conditions, DA is not synthesized and DAF-12 interacts with the DIN-1/CoR to repress the expression of let-7 miRNAs, blocking the transition to L3 and allowing dauer arrest (Bethke et al., 2009). In Drosophila, let-7 expression correlates with the levels of ecdysone (Bashirullah et al., 2003; Pasquinelli et al., 2000; Sempere et al., 2003). Moreover, it has recently been shown that EcR binds three response elements in the let-7
C locus which encodes the co-transcribed miRNAs let-7, miR-125 and miR-100 (Luhur et al., 2013). These ecdysone response elements are essential for ecdysone to induce let-7
C expression in imaginal discs and salivary glands during the larval-to-adult transition. In the CNS, removal of these elements reduces but does not eliminate let-7
C expression, suggesting that other factors in addition to EcR are involved in regulating this locus. Similarly, let-7 isoforms start to increase from pre-metamorphosis in Japanese flounder and peak at pro-metamorphosis (Fu et al., 2013). Incubation of flounder larva with exogenous T3 from pre-metamorphosis increases the levels of all let-7 isoforms. In zebrafish, let-7 and miR-125 increase at days 2–3 post-fertilization (Ouchi et al., 2014; Pasquinelli et al., 2000), coinciding with an increase in the levels of TR-β (Liu and Chan, 2002). Interestingly, total levels of T4 and T3 remain constant during embryogenesis and increase at 5 days post fertilization, after an increase in the levels of TR-β (Chang et al., 2012b). It is unknown if TR-β is a direct target of T3 in zebrafish, but the incubation with exogenous T3 induces TR-β (Liu and Chan, 2002). Considering that this regulation is conserved in amphibians and mammals, differential regulation of deiodinases or other factors involved in signaling could explain the different pattern between TR-β and T3 levels. In any

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case, the direct regulation of let-7 and miR-125 by T3/TR has not been shown in these species. ChIP studies could be used to determine if these miRNAs are directly regulated by TRs during developmental transitions. In contrast to let-7, hormonal regulation of Lin-28 and Lin-41 has not been studied during development. Whether ecdysone regulates the levels of Lin-28 has not been determined. However, it is interesting that Lin-28 protein in whole extracts increases in the pupa when ecdysone levels are high (Moss and Tang, 2003). Interestingly, in zebrafish lin-28a and lin-28b levels are high during the first day post-fertilization and then decrease (Ouchi et al., 2014) when the levels of TR-β start to increase at the embryo-tolarval transition (Liu and Chan, 2002). The regulation of lin-28 and lin-41 by thyroid hormones has not been studied in zebrafish or Xenopus. This regulation, direct or indirect, would be an interesting mechanism to control the transition of stem and progenitor cells from self-renewal to differentiation. It was recently shown that the levels of lin-28 in rat testis are modified after removal of the hypophysis (Sangiao-Alvarellos et al., 2015). In long-term hypo-physectomized rats, which cannot synthesize gonadotropins, lin-28a increases and lin-28b decreases in testis compared to untreated animals, suggesting differential regulation of lin-28 genes. In a dwarf rat strain (model of growth hormone (GH) deficiency), the levels of Lin-28a and Lin-28b increase compared to wild-type animals (Sangiao-Alvarellos et al., 2015). Considering the relation between growth and developmental timing, this interesting result suggests that GH could negatively regulate lin-28 expression, at least in testis. It will be interesting to determine if this regulation is direct, if it occurs in other tissues and if it controls the timing of lin-28 down-regulation during differentiation and developmental transitions. In contrast to regulation by gonadotropins and GH, the levels of lin28 in testis were not modified after deprivation of adrenal and TH in adults (Sangiao-Alvarellos et al., 2015). Whether these hormones control the levels of lin-28 in other tissues or during pregnancy has not been studied. Metamorphosis in amphibians could be a good experimental model to study the interaction among heterochronic genes and hormones such as insulin, growth and thyroid hormones. An approach to understanding the function of Lin-28 is to determine the transcripts that are directly regulated by Lin-28. Recent experiments using Crosslink Immunoprecipitation (CLIP) followed by transcriptomic analyses have revealed several targets of Lin-28 in human and mouse embryonic stem cells and in HEK293 cells (Cho et al., 2012; Graf et al., 2013; Hafner et al., 2013; Wilbert et al., 2012). These analyses could reveal a link between Lin-28 and transcripts related to hormonal signaling, in addition to the known roles of Lin-28 in glucose metabolism and let-7 biogenesis. In that same line, the DAF-12-interacting protein 1 (Din-1) is bound to Lin-28 in L1-stage samples in C. elegans (Stefani et al., 2015). Din-1 is a co-repressor that interacts with DAF-12 under unfavorable conditions to promote dauer diapause (Ludewig et al., 2004), but the effect of Lin-28 on Din-1 protein levels is not known. Interestingly, a search in Lin-28-CLIP databases of mouse ESCs and HEK293 reveals the thyroid hormone receptor interactor 11 (TRIP11) as a Lin-28-bound transcript (Cho et al., 2012; Hafner et al., 2013). The expression or role of TRIP11 during Xenopus metamorphosis or mouse development, have not been studied. However, this result suggests that Lin-28 could be directly connected to the hormonal axis by regulating the levels of factors that bind the TH receptor. The possible cross-regulation between hormonal signaling factors and heterochronic genes during developmental transitions could be a strategy to coordinate physiological status with intrinsic programs of stem and progenitor cells (Fig. 5). The comparison among expression patterns of heterochronic genes and the effect

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of hormones on these genes during metamorphosis in different tissues will provide insights into the mechanisms that communicate intrinsic programs with physiological signals.

4. Regulation of transitions in mammals and consequences on regeneration and diseases Regeneration abilities decrease with aging in animals and the mechanisms involved in this reduction have only recently started to be elucidated. We briefly review and focus the discussion on the role of heterochronic genes and thyroid hormones in regeneration in non-mammals and mammals. Axon regenerative ability in C. elegans decreases during development and, recently, one role of heterochronic genes has been described. In anterior ventral microtubule (AVM) axons, let-7 lossof-function increases axon regeneration after laser injury (Zou et al., 2013). lin-41 mutations suppress this let-7-enhancing regeneration phenotype, suggesting that Lin-41 is one of the main factors downstream of let-7. In addition, Lin-41 overexpression and lin-29 loss-of function increase regeneration abilities, indicating that Lin-41/let-7 regulate Lin-29 to control AVM regeneration. In zebrafish, the expression of Lin-28 is induced early after retinal damage in Müller glia. Morpholino knock-down experiments indicate that this expression is required for proliferation and de-differentiation of Müller glia during the regenerative process (Ramachandran et al., 2010). A role of heterochronic genes in amphibian regeneration has not been described. The expression of heterochronic genes after limb or tail amputation, or after spinal cord injury is not known. Considering that regeneration is associated with the presence of stem and progenitor cells, it is tempting to speculate that stemness-related heterochronic genes such as Lin-28 and Lin-41 could mediate regeneration in tadpoles before metamorphosis. Future work is necessary to determine the expression in these tissues and the role of heterochronic genes on the regeneration capabilities of Xenopus. Interestingly, regeneration abilities in Xenopus spinal cord decrease during metamorphosis, concomitant with the increase in T3 levels (Beattie et al., 1990; Gaete et al., 2012; Moreno et al., 2014; Muñoz et al., 2015). Long incubations of animals with T3 or methimazole, inhibitor of T3 synthesis, showed that spinal cord regeneration is associated with developmental stages and several T3-regulated genes were identified that could mediate this ability (Gibbs et al., 2011). As described before, T3 regulates proliferation and differentiation of stem and progenitor cells and this effect could be crucial for regeneration. In mice, both Lin-28 and TH have effects on regeneration. Lin28 improves mammal hair regrowth and tissue repair at post-natal stages (Shyh-Chang et al., 2013). Lin-28 increases glycolysis and oxidative phosphorylation by regulating the translation of several metabolic enzymes. It has been suggested that it keeps animals in a juvenile stage. However, Lin-28 alone is not able to promote tissue repair in adults, indicating that the competence to respond to Lin-28 is lost after post-natal stages and other inhibitor factors repress adult regeneration. Alternatively, Lin-28-induced regeneration could be due to the preservation of a young state and not to a direct effect on regeneration. On the other hand, T3 reduces axonal regenerative capacity of Purkinje cells in organotypic cultures derived from newborn mice (Avci et al., 2012). In this model, the T3-target gene krüppel-like factor 9 (Klf-9) mediates the inhibitory effect of T3 in regeneration. However, in other cases, TH stimulate regeneration and the differences could be due to doses used, specific action on different cell types and the time of exposure after damage (Bhumika and Darras, 2014). A functional link between TH and heterochronic genes has not been studied in any of these systems and it would be

Please cite this article as: Faunes, F., Larraín, J., Conservation in the involvement of heterochronic genes and hormones during developmental transitions. Dev. Biol. (2016), http://dx.doi.org/10.1016/j.ydbio.2016.06.013i

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F. Faunes, J. Larraín / Developmental Biology ∎ (∎∎∎∎) ∎∎∎–∎∎∎

interesting to determine if positive roles of Lin-28 on regeneration occur only before the endogenous peak of T3 or if they are lost after T3 exposure during the perinatal period.

5. Conclusions Based on the findings described in this review, we propose a general framework for conserved mechanisms among species that regulate developmental transitions. This regulation involves the interaction of environment, sensor tissues, hormones and heterochronic genes that impact on stem and progenitor cells present in the different embryonic and post-embryonic tissues that will undergo remodeling (Fig. 5). Environmental signals are integrated by the organism mainly in sensor tissues (sensory neurons, fat body and hypothalamus, Fig. 5, red) that also integrates inputs from other tissues and transform these into hormonal signals (PTTH, ILP, CRF, TRH, ACTH, TSH). These hormones regulate the function of endocrine glands (endocrine XXX cells, prothoracic gland, adrenal gland, thyroid gland, Fig. 5, blue). Endocrine glands secrete hormones such as DA, Ecdysone, GC and TH that, depending on the presence of transporters, receptors, co-factors and activating enzymes, regulate proliferation and differentiation of stem and progenitor cells (Fig. 5, green). Importantly, all these layers of regulation are present in the three organisms discussed in this review (C. elegans, Drosophila, Xenopus) showing the evolutionary conservation of this general mechanism involved in the regulation of developmental transitions. Throughout this hormonal program, the heterochronic gene network, including transcription factors, RNA-binding proteins and miRNAs, simultaneously regulates multiple target genes and activates specific transcriptional programs. Links between these two branches are starting to be revealed, such as the regulation of let-7 by ecdysone and TH and the possible regulation of hormonal signaling-related proteins by Lin-28. We expect that more links will be identified in future, specifically during developmental transitions. Significantly, these two branches also control mammalian stem and progenitor cells in vivo and in vitro and they could be involved in controlling perinatal development and the timing of puberty. These interactions are probably crucial to coordinate transitions in different tissues avoiding continuous proliferation or premature differentiation in some tissues compared to others, which could result in death or decreased fitness. Recent work has started to reveal the influence of environmental factors and we have mainly reviewed food availability and how it regulates transitions through communication among different progenitor cells. In addition to nutrition, other factors, such as circadian clocks, temperature, and stress by predators, must be integrated and transformed into hormonal signals, which regulate cell decisions. Future work in vertebrates promise to reveal similarities and differences among animals and how these mechanisms are related to disorders and regeneration abilities in mammals. We propose that the conserved integration and the function of these networks in animal stem and progenitor cells in vivo is crucial for the normal timing of development and transitions at the organism level.

Acknowledgements We thank Esteban Contreras, Gabriela Edwards-Faret, Daniel Guzmán, Dasfne Lee-Liu, Emilio Méndez and Victor Tapia for their critical reading of the manuscript, Alicia Minitti and Daniela Rebolledo for C. elegans images, Esteban Contreras and Alvaro Glavic

for Drosophila images, Gabriela Edwards-Faret for Xenopus image and Daniel Guzmán for his help with the analysis of CLIP published data. This work was funded by research grants from FONDECYT “Iniciación” N° 11130564, MINREB RC120003, CARE Chile UC-Centro de Envejecimiento y Regeneración PFB 12/2007 and ICGEB (CRP/CHI-13–01).

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