LPPRs) in the brain

Biochimica et Biophysica Acta 1831 (2013) 133–138

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Review

Current views on regulation and function of plasticity-related genes (PRGs/LPPRs) in the brain☆ Ulf Strauss, Anja U. Bräuer ⁎ Institute of Cell Biology and Neurobiology, Center for Anatomy, Charité — Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany

a r t i c l e

i n f o

Article history: Received 18 June 2012 Received in revised form 9 August 2012 Accepted 10 August 2012 Available online 19 August 2012 Keywords: Central nervous system Transcription Epilepsy Filopodia formation Excitatory synaptic transmission

a b s t r a c t Plasticity-related genes (PRGs, Lipid phosphate phosphatase-related proteins LPPRs) are a defined as a subclass of the lipid phosphate phosphatase (LPP) superfamily, comprising so far five brain- and vertebrate-specific membrane-spanning proteins. LPPs interfere with lipid phosphate signaling and are thereby involved in mediating the extracellular concentration and signal transduction of lipid phosphate esters such as lysophosphatidate (LPA) and spingosine-1 phosphate (S1P). LPPs dephosphorylate their substrates through extracellular catalytic domains, thus making them ecto-phosphatases. PRGs/LPPRs are structurally similar to the other LPP family members in general. They are predominantly expressed in the CNS in a subtype specific pattern rather than having a wide tissue distribution. In contrast to LPPs, PRGs/LPPRs may act by modifying bioactive lipids and their signaling pathways, rather than possessing an ecto-phosphatase activity. However, the exact functional roles of PRGs/LPPRs have just begun to be explored. Here, we discuss new findings on the neuron-specific transcriptional regulation of PRG1/LPPR4 and new insights into protein–protein interaction and signaling pathway regulation. Further, we start to shed light on the subcellular localization and the resulting functional modulatory influence of PRG1/LPPR4 expression in excitatory synaptic transmission to the established neural effects such as promotion of filopodia formation, neurite extension, axonal sprouting and reorganization after lesion. This range of effects suggests an involvement in the pathogenesis and/or reparation attempts in disease. Therefore, we summarize available data on the association of PRGs/LPPRs with several neurological and other diseases in humans and experimental animals. Finally we highlight important open questions and emerging future directions of research. This article is part of a Special Issue entitled Advances in Lysophospholipid Research. © 2012 Elsevier B.V. All rights reserved.

1. Introduction Plasticity-related genes (PRGs) also referred to as lipid phosphate phosphatase-related proteins (LPPRs), are a brain-specific class of lysophospholipid-modifying proteins [1,2]. The first identified member, namely PRG1/LPPR4, we found in hippocampal lesions of adult mice as part of a study focusing on molecular mechanisms of plasticity [2]. Since then, in silico analysis predicted four other proteins named PRG2-5/LPPR3, -1, -2, and -5, which show high homology to PRG1/LPPR4. These are as yet less characterized [3,4]. Individual expression patterns during brain development in mice gave rise to the assumption that PRGs/LPPRs have different regulatory mechanisms and neuronal functions in the CNS [1]. Based on their high sequence homology, structural similarities and functional characteristics in modulating the effects of bioactive phospholipids, PRGs/LPPRs have been

☆ This article is part of a Special Issue entitled Advances in Lysophospholipid Research. ⁎ Corresponding author. Tel.: +49 30 450528405; fax: +49 30 450528902. E-mail address: [email protected] (A.U. Bräuer). 1388-1981/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.bbalip.2012.08.010

classified as a novel subgroup within the lipid phosphate phosphatase (LPP) superfamily. LPPs are integral membrane proteins characterized by six transmembrane domains and three extracellular loops with conserved active sites important for ecto-enzymatic activity. These cell surface-located ecto-phosphatases modulate the affinity of the extracellular phospholipid LPA and related substrates to their specific receptors [5]. In contrast to other ubiquitously expressed LPPs, PRG1/LPPR4 shows vertebrate- and brain-specific expression. Since upregulated PRG1/LPPR4 expression in developing and lesioned brain of mice was associated with axonal outgrowth and regenerative sprouting, PRG1/LPPR4 is considered a putative regulator of neuronal plasticity. Functional analyses of PRG1/LPPR4 with regard to its ecto-enzymatic activity revealed increased extracellular LPA degradation and attenuation of LPA-induced neurite retraction after PRG1/LPPR4 overexpression in neuroblastoma cells, giving evidence for PRG1/LPPR4 being a potent modulator of phospholipid-mediated signaling [2]. Characterizing the recently generated PRG1/LPPR4 knock-out mouse will aid understanding of neuron-specific functions and signaling of PRG1/LPPR4 in the developing and adult brain. Interestingly, there is no indication of similar ecto-phosphatase-related properties in the other PRG/LPPRs members so far [3,6].

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2. Expression and regulation 2.1. PRG/LPPR expression during brain development PRG1/LPPR4 mRNAs exhibit dominant expression in late mouse embryonic stages, specifically in the hippocampal region. At embryonic day 19 (E19), the mRNA is detected in the subventricular zone and hippocampal anlage. After birth, mRNA expression increases dramatically in several neuronal brain areas such as the neocortex, hippocampus and cerebellum. The transcript increase is detectable until postnatal day 20 and then decreases to a stable level in adulthood [2]. In addition, PRG1/LPPR4 mRNA is differentially regulated in the embryonic development of the medial ganglionic eminence, putatively governing cortical interneuron or other GABA-ergic cell development and fate [7]. However, the interneuronal expression must be transient, because in adult brains of rats and mice PRG1/LPPR4 locates exclusively to glutamatergic neurons mainly in the forebrain and cerebellum [8,9]. However, PRGs/LPPRs also seem to be regulated by neuronal development, as in the case of PRG3/LPPR1, which is reduced in the course of development [10], most likely due to the increase in basal neuronal activity. Specifically, PRG3/LPPR1 mRNAs are expressed during mouse embryonic development as early as E14 in the dorsal cortex, cingulated cortex and anlage of the hippocampus. At E16, PRG3/LPPR1 mRNAs are strongly detectable in the cortical plate of the cortex and moderately expressed in the marginal zone and intermediate zones. This pattern remains unchanged until birth. After birth, PRG3/LPPR1 is expressed in all cortical layers. In the adult, brain tissue expresses PRG3/LPPR1 mRNA homogenously [3,10]. The last, for the time being, PRG/LPPR family member, PRG5/LPPR5, and its splice variant, appears likewise developmentally regulated, because it is expressed in fetal human brain [11] and during spinal cord development. Furthermore, PRG5/LPPR5 shows the closest relation to PRG3/LPPR1 with more than 73% homology at the nucleotide level and 55% identical amino acid residues [4]. In the adult brain, PRG5/LPPR5 mRNA is highly expressed in the dentate gyrus, cornu ammonis (CA1–CA3) and olfactory bulb. Lower signals are detected in the cortex, stratum radiatum, cerebellum and striatum. Other brain regions such as the thalamus, pons and hypothalamus showed only a weak expression level (GeneNote analysis, NCBI profile graph; [4]). 2.2. Transcriptional regulation of PRG1/LPPR4 PRG1/LPPR4 is vertebrate-specific and almost restricted to the CNS. The expression pattern seems strictly regulated during development and following brain lesions [1–3]. In more adult stages, in particular, PRG1/LPPR4 was exclusively present on glutamatergic neurons [8]. In order to identify the mechanisms of the obviously tight spatial and temporal transcriptional control, the group of Robert Nitsch has started to characterize the PRG1/LPPR4 promoter (AliBaba2.1 (gene-regulation.com)) [12]. PRG1/LPPR4 is transcribed via a type null core promoter containing neither TATA box nor initiator elements. As is common for a type null core promoter, the PRG1/LPPR4 promoter has multiple transcription start sites. A second ATG is located at position +148 in mice and rats, and at position +145 in humans, which imply the existence of a second, shorter PRG1/LPPR4 protein lacking the N-terminal 49 amino acids. Interestingly, only PRG1/LPPR4 and no other LPP-super family member possesses an N-terminal extension. However, the functional role of this N-terminal elongation remains to be elucidated. Furthermore, one sequence element of around 450 bp mediates specific neuronal transcription in human and rodent PRG1/LPPR4 promoter [12]. In these 450 bp are located minimal promoter (h −300/+143; m −297/+ 145) transcription factor binding sites for Sp1 (specificity protein 1) and CRE (cAMP-responsive element), as are located and confirmed by EMSA shift assays [12]. PRG1/LPPR4 was also identified as a potential

target of CREB regulation in two other screening studies [13,14]. Both, Sp1 and CREB are widely expressed transcription factors. So far, it is unclear whether CREB and/or Sp1 govern the specific neuronal stimulation on the minimal promoter or if another binding site on this fragment mediates the neuronal specificity of PRG1/LPPR4 and CREB together with Sp1 to amplify this transcriptional stimulation. Here good candidates were members of the basic helix-loop-helix (bHLH) transcription factor family, which are involved in neuronal differentiation and maturation. In this context, Nex1 (Math2/NeuroD6) was shown to bind directly to at least one E-Box in the minimal promoter region of PRG1/ LPPR4, which mediates neurite outgrowth in PC12 cells [15]. Moreover the expression pattern of NEX1 and PRG1/LPPR4 overlaps in their spatial and temporal progress. In contrast, Nex1 deficiency induces no change in PRG1/LPPR4 expression and localization [12]. However, the E-box motif for Nex1 binding in rat [15] is not conserved in mouse and human. This discrepancy has to be elucidated in further studies. 3. Functional implications 3.1. PRG1/LPPR4 C-terminus: protein–protein interaction The predicted structural model of human PRG1/LPPR4 shows high homology to LPP-1 considering the six transmembrane domains, intracellular presence of C- and N-terminus and three extracellular loops with three putative catalytic regions. Unlike other LPPs, PRG1/LPPR4 has a unique, long – 400 amino acid-spanning – hydrophilic C-terminus that might play a role in intracellular interactions and signaling [2]. In this context, it has been shown that PRG1/LPPR4 binds equimolar amounts of calmodulin (CaM) with relatively high affinity (Kd=8 nM), which is comparable with that of CaM-regulated enzymes such as CaM kinases [9]. Furthermore, the binding domain is most probably located between amino acid residues 554–588 at the C-terminus. This region is conserved between rat, mouse and human PRG1/LPPR4. Moreover, the results suggested that Trp559 and Ile578 are the essential hydrophobic residues anchoring PRG1/LPPR4 to the hydrophobic pockets of CaM [9]. The authors suggest that PRG1/LPPR4 regulates excitatory synaptic transmission and that this regulation may be modulated via PRG1/LPPR4–CaM binding and controlled by changes in the concentration of intracellular Ca2+ [9] (Fig. 1). Another study reports that the TRIM67 (tripartite motif-containing proteins) regulates PRG1/LPPR4 and 80K-H (protein kinase C substrate 80K-H, also known as glucosidase II ß), which is involved in the activation of Ras. This suggests that TRIM67 negatively regulates Ras in cell proliferation and differentiation of neural precursor cells. In the neuroblastoma cell line N1E-115, TRIM67 directly interacted with 80K-H. Due to the lack of a direct interaction between TRIM67 and PRG1/LPPR4, the authors suggest that TRIM67 interacts with PRG1/LPPR4 via an unknown modification or adaptor molecule [16]. Furthermore, overexpression of TRIM67 may stabilize endogenous PRG1/LPPR4, indicating that neurite outgrowth by overexpression of TRIM67 could be due to stabilization of PRG1/LPPR4 [16]. Interestingly, calmodulin binds to K-Ras and this interaction may modulate Ras signaling [17,18]. Further investigation should clarify whether PRG1/LPPR4 plays a role in this interaction and therefore in controlling Ras signaling. Regulation of protein activity is often modulated by reversible phosphorylation, and information about specific sites of phosphorylation is vital for understanding cellular signaling pathways. For this reason, the identification of phosphorylation sites in PRG1/LPPR4 has generated much interest. One large scale phosphoproteome analysis in distinct subcellular compartments of brain cells identified PRG1/LPPR4 phosphorylation on Ser347 prepared from synaptic vesicles fraction and PRG1/LPPR4 phosphorylation on Thr417 in postsynaptic density fraction [19] (PRG1 Accession No.: Q7TME0). We assume that these different phosphorylation sites could be involved in the regulation of PRG1/LPPR4 localization at postsynaptic sites (Fig. 1). PRG1/LPPR4 was also present as a phosphoprotein in the murine WEHI-231 B lymphoma cell line. The sites of phosphorylation were

U. Strauss, A.U. Bräuer / Biochimica et Biophysica Acta 1831 (2013) 133–138

presynaptic terminal

glutamate

? G-protein

LPA

2

LPA

LPA2

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LPA

LPA LPA

LPA

PRG1

LPA

PR4

/ LPP P

LPA

R4

LPA2

PRG1/ LP

Th

lin

calmodu

r 417

?

?

?

7

34

r Se

P

Ca2+

Ca

activity against any of the well-characterized LPT substrates, because PRG3/LPPR1 exerts no enzymatic activity [3,26]. Functional tests suggest that also PRG5/LPPR5 contributes to an mDia1- and Cdc42-independent pathway to promote actin-enriched protrusions and neurite growth in the N1E-115 cell line and immature cortical neurons [4]. However, its closest member, PRG3/LPPR1, has been reported to act independent of the filopodia-forming mDia2 and Cdc42 [26]. Whether PRG3/LPPR1 and/or PRG5/LPPR5 activate an alternative pathway is under investigation. PRG5/LPPR5 growth-promoting activity is located at the C-terminus, which needs to be localized near the plasma membrane. Only two obvious motifs present in both PRG3/LPPR1 and PRG5/ LPPR5 (CVVXNFKG and PXXESPLE), known as PEST domain sequences were identified. PEST sequences are hypothesized to act as a signal peptide for protein degradation. Furthermore, PRG5/LPPR5 contributes to interference mechanisms overcoming LPA- and Nogo-A–induced RhoA activation and, subsequently, neurite retraction in vitro [4]. Taken together, the dynamic developmental expression of PRGs/ LPPRs suggests a role in the organization of neuronal development at the molecular level. 3.3. PRGs/LPPRs: LPA-modifying proteins

7 34

r Se

P

LPA

2+

135

postsynaptic glutamatergic neuron Fig. 1. Schematic drawing of an excitatory synapse with the proposed mode of PRG1/ LPPR4 action. The drawing depicts the synaptic transmission in hippocampal glutamatergic neurons. As shown by us and others [8,9] PRG1/LPPR4 is located at the postsynaptic side and may control bioactive lipid content in the synaptic cleft by uptake into the intracellular compartment. Whether the phosphorylation status (in green) of PRG1/LPPR4 is required for this uptake has to be elucidated in further experiments [19]. Another open question is the PRG1/LPPR4 interaction together with calmodulin [9] and if this interaction can regulate the vesicle transport dependent or independent of LPA. Thus, LPA and other bioactive lipids, able to signal via presynaptic LPA2-receptors [35] to the synaptic cleft, could be controlled by postsynaptic PRG1/ LPPR4 (adapted from [8]).

identified on Ser218 [20]. At present, it is unclear whether PRG1/LPPR4 expression and/or the phosphorylation in this non-neuronal cell line are due to the lymphoma. Phosphorylation as a new aspect of PRG1/LPPR4 activity regulation has not been studied yet. It might change protein localization, oligomeric or conformational state, which might influence the activity of the protein. It would be interesting to know, how phosphorylation changes PRG1/LPPR4 and what effect it has on its activity. The identification of kinase(s) which phosphorylate PRG1/LPPR4 would lead to the elucidation of signaling pathways regulating PRG1/LPPR4 and lipid signaling. 3.2. PRG3/LPPR1 and PRG5/LPPR5 shape neurons Stabilization or destabilization of the cytoskeleton by intracellular signaling cascades is controlled by extracellular cues. Among others, phospholipids such as lysophosphatidic acid (LPA) and sphingosin1-phosphate (S1P) mediate cell motility, growth, proliferation and survival by binding on specific G protein-coupled receptors to activate multiple signal transduction pathways [21–24]. Modulation of phospholipid signaling occurs by members of the lipid phosphatase/ phosphotransferase family (LPT, also known as PAP2) [25]. One LPT subgroup consists of PRGs/LPPRs [2]. Two of the five PRGs/LPPRs, PRG3/LPPR1 and PRG5/LPPR5, have been shown to influence neuronal morphology. Functional tests of PRG3/LPPR1 suggested a role during neurite outgrowth: PRG3/LPPR1 overexpression induced the formation of actin-rich, dynamic filopodia in several cell lines such as N1E-115, HeLa, and COS-7 cells [3,26]. Interestingly, this induction was not mediated by cdc42 (cell division control protein 42 homolog) or Rif, a Rho-family GTPase, and occurred independently of the Arp2/3 complex (actin-related protein 2/actin-related protein 3 complex; [26]). The neurite outgrowth was also not directly linked to phosphatase

All PRGs/LPPRs are highly homologous to LPPs regarding their N-terminus, in particular conserved ecto-phosphatase domains. Functionally, overexpression of PRG1/LPPR4 attenuates LPA-induced neurite collapse in neuronal cells [2]. Point mutating his252 to lysine in the conserved catalytic domain D2 of PRG-1 abolished this protective effect (Fig. 2 marked with a black asterisk). Further tests showed an increase in MAG in PRG-1 overexpressing cells, whereas the point mutated PRG1/LPPR4 version showed no alteration in LPA-MAG levels [2]. However, since sequence analysis of three putative catalytic sites (Fig. 2; D1, D2, and D3) revealed few non-conservative substitutions in residues, which are essential for the ecto-phosphatase activity of LPPs [27], equivalent catalytic properties of PRG1/LPPR4 are unlikely. In this context, PRG1/LPPR4 did not catch up with LPP3 in the degradation of radioactively labeled oleyl-LPA in a direct comparison [28]. Other members of the PRG/LPPR family, PRG3/LPPR1 and PRG5/LPPR5, show no ecto-phosphatase activity, which is confirmed by several groups [3,4,11,26]. Why PRG1/LPPR4 overexpressing cells show LPA degradation products while PRG3/LPPR1 and PRG5/LPPR5 do not remains to be elucidated. A clear difference between PRG1/LPPR4 and PRG3/LPPR1, as well as PRG5/LPPR5, is the long C-terminus of PRG1/LPPR4 of around 400 aa. To date, there is no evidence that the intracellularly located C-terminus of PRG1/LPPR4 is involved in dephosphorylation of extracellular LPA. The controversial issue of the ecto-phosphatase activity of PRG1/ LPPR4 might be solved by the assumption that PRG1/LPPR4 regulates lipid signaling by alternate biological activities, i.e. differing from dephosphorylation for e.g. protecting neurons from LPA-mediated neurite retraction enabling axonal elongation under phospholipidrich conditions. Despite the lack of catalytic residues, critical for dephosphorylation, PRG1/LPPR4 retains sequences, required for the capacity to interact with their lipid substrates [6]. Resolving the discrepancy between the above findings and thereby clarifying the exact mechanism of action of PRGs/LPPRs in protein and phospholipid metabolism in the brain requires further investigation. 3.4. PRG1/LPPR4 and synaptic transmission The site of PRG1/LPPR4 action has recently been extended from axons (in neural development and after lesion) to dendrites of pyramidal neurons. Specifically, PRG1/LPPR4 in hippocampal neurons localizes exclusively at excitatory postsynapses of dendritic spines in rats [9] and mice [8]. In detail, PRG1/LPPR4 colocalized with molecules specific for the postsynaptic density of glutamatergic neurons such as ProSAP2 and Homer1, but not Gephrin, a marker for GABAergic contacts. Moreover, the immunogold signal of PRG1/

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Fig. 2. Alignment of the enzymatic active domains. Alignment of the catalytic domain sequences (D1, D2, and D3) from human PRGs/LPPRs with human LPP-1. Underlined are sequence homologies between a minimum of two candidates. Marked with red arrows and in red letters are residues of conserved amino acids required for the enzymatic activity e.g. for LPP-1. The his252, which we point mutated to lysin, in the catalytic domain D2 is marked with a black asterisk.

LPPR4 bordered the synaptic cleft [8]. This subcellular localization pattern suggests that PRGs/LPPRs are involved in the modulatory control of excitatory synaptic transmission in the hippocampus. Indeed, deletion of PRG1/LPPR4 results in augmented excitatory field potentials following Schaffer collaterals stimulation enhanced evoked synaptic current and higher mEPSC frequency, through not amplitude-specifically for excitatory transmission, which could be rescued by PRG1/LPPR4 but not by a mutated PRG1/LPPR4 disabled to interact with lipid phosphates by an exchange from histidine to lysine at position 253. Changes to hippocampal network excitability are mimicked by excess supply of LPA and fully reverted in the absence of LPA2-receptor. Regarding the molecular mechanism this study adds evidence to a PRG1/LPPR4 action apart from its potential residual enzymatic activity [2]. Although the roughly linear relationship between protein expression and its electrophysiological action argues against an enzymatic function of PRG1/LPPR4 and PRG1/ LPPR4 enzymatic activity is hampered by several non-conservative substitutions in the extracellular domains involved in catalysis [28], PRG1/LPPR4 appeared still effective in the control of LPA levels. Further, a lack of PRG1/LPPR4 in neurons significantly limits the uptake of bioactive lipids. Thus, PRG1/LPPR4 function may have evolved to “sensor-like” or receptor/transporter-like activities. Such functional shifts were shown for other “enzymes” as a result of mutations in critical catalytic residues in active sites [29]. From the synopsis of these data we hypothesized, that PRG1/ LPPR4 interferes from the postsynaptic side with the glutamatergic signal transduction by interacting with lipid phosphates in the synaptic cleft [8] (Fig. 1). 4. PRGs/LPPRs and neurological disease 4.1. Epilepsy In line with the synaptic impact of PRG1/LPPR4 described in the previous paragraph, deletion of prg1/lppr4 in mice led to hypersynchronized activity and preictal events at postnatal day 20 in all PRG1 −/−/LPPR4 −/− mice investigated. 50% of the KO mice developed focal electrographic ictal events with a secondary generalization accompanied by tonic–clonic seizures developing to status epilepticus and death [8]. This indicates that the lack of PRG1 results in an alteration of synaptic transmission subsequently leading to juvenile epileptic seizures. On the other hand, seizures themselves can change PRG1/LPPR4 levels as shown by a number of studies using flurothyl to induce single or recurrent neonatal seizures, which led to cognitive deficits and sprouting in mossy fibers accompanied by a trend towards immediate PRG1/LPPR4 mRNA increase [30]. A subsequent temporal analysis revealed increased PRG1/LPPR4 protein levels in the hippocampus 7 and 14 days after the last seizure. Interestingly, PRG1/LPPR4 upregulation is not restricted to the hippocampus, but also present in the cortex 7 days after the last seizure [31]. Together with our findings in the PRG1 −/−/LPPR4 −/− mouse model this may indicate a compensatory protective response against developmental

seizure induced brain damage. However, given the role of mossy fiber sprouting in the post-seizure hippocampus and the putative involvement of PRG1/LPPR4 in that process, PRG1/LPPR4 might also be detrimental after seizures, contributing to post-seizure cognitive deficits observed in mice and men. The seizure-induced upregulation of PRG1/LPPR4 appears to persist up to at least 35 days after the last seizure in hippocampus and cortex [32]. Moreover, inhibiting Cathepsin B not only prevented the upregulation of PRG1/LPPR4 but also the cognitive and motor deficits a month after recurrent seizures. This further suggests a participation of PRG1/LPPR4 in the molecular mechanisms underlying developmental seizure-induced long-term effects, e.g. on behavioral dysfunction. In accordance with its suggested developmental regulation by neuronal activity, PRG3/LPPR1 was transiently downregulated in the hippocampus after kainite-induced seizures [3]. In line with this flurothyl induced recurrent seizures also transiently downregulated PRG3/LPPR1 in rat cerebral cortex [32]. 4.2. Neurotrauma As in neuronal development, PRG1/LPPR4 expression is upregulated in the lesioned brain of mice and is associated with axonal outgrowth and regenerative sprouting. Therefore, PRG1/LPPR4 is considered a regulator of neuronal plasticity in the CNS [2]. However, PRG1/LPPR4 is also upregulated in regrowing peripheral nerves e.g. after transection of facial nerve fibers. There, interestingly, the levels of PRG1/LPPR4 after lesion were correlated to an augmented early regenerative response and enhanced recovery of function [33]. Together, this indicates a role of PRG1/LPPR4 in promoting outgrowth capability and functional neuronal regeneration. Regenerative activity of PRG1/LPPR4 might not be restricted to the CNS as suggested by findings of PRG1/LPPR4 upregulation in after other lesions such as those in human liver carcinoma cells after mercury exposure [34]. The posttraumatic PRG1/LPPR4 upregulation might be seen as a protective strategy, given the putative increase of local LPA by the upregulation of autotaxin in neurotrauma [35] and the suggested modulatory PRG1/LPPR4 activity [2]. It is worth noting that the results of the above (4.1. and 4.2.) animal studies might be conferrable to human disease since haploinsufficiency of the PRG1/LPPR4-containing sequences of chromosome 1q is frequently associated with severe psychomotorical retardation and seizures ([36] and Table 1 therein). 4.3. Parkinson's disease In a study performed directly on human material, PRG1/LPPR4 was found differentially regulated in the substantia nigra of clinically and histologically confirmed Parkinson's disease patients. This is of particular interest because it maps to PARK 10 on the 1q chromosome [37]. The PARK 10 region is linked to risk and age of onset in Parkinson's disease [38]. An involvement of PRGs/LPPRs in motor control is further suggested by the finding of prominent PRG1/LPPR4 expression in the caudate putamen of adult rats [9].

U. Strauss, A.U. Bräuer / Biochimica et Biophysica Acta 1831 (2013) 133–138 Table 1 PRGs (LPPRs): their names and chromosomal localization.

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excitatory phenomenon, will advance our understanding of the role of PRGs/LPPRs in the pathogenesis of seizures. In this context, little is known on the relevance of PRG2/LPPR3 and PRG4/LPPR2. Of utmost interest are the precise mechanisms of PRG/LPPR action in light of the absence of the essential amino acids needed for a phosphatase motif. These putatively contain indirect PRG/LPPR actions i.e. stimulating LPP activities, binding lipid phosphates, dephosphorylation or phosphotransferase activity. Growing evidence for an involvement of PRGs/LPPRs in several diseases underlines the need for further research. In particular the role of PRGs/LPPRs within the entity of brain ecto-phosphatases with regard to tumor progression or metastasis needs to be clarified.

Names

Species Chromosome (location)a

Accession no.a

PRG1 Plasticity-related gene 1 LPPR4 (LPR4) Lipid phosphate phosphatase-related protein type 4 PRG2 Plasticity-related gene 2 LPPR3 (LPR3) Lipid phosphate phosphatase-related protein type 3 PRG3 Plasticity-related gene 3 LPPR1 (LPR1) Lipid phosphate phosphatase-related protein type 1 PRG4 Plasticity-related gene 4 LPPR2 (LPR2) Lipid phosphate phosphatase-related protein type 2 PRG5 Plasticity-related gene 5 LPPR5 (LPR5) Lipid phosphate phosphatase-related protein type 5 isoform 1 PAP2d_v1 and PAP2d_v2 Phosphatidic acid phosphatase type 2

Rat

Chromosome 2 (2q41) Human Chromosome 1 (1p21.2) Mouse Chromosome 3 (3 55.0 cM) Rat Chromosome 7 (7q11) Human Chromosome 19 (19p13.3) Mouse Chromosome 10 (10)

NP_001001508.1

Rat

5

NP_958428.1

Acknowledgments

9

NP_060223.2

4 (4

NP_848871.1

This work was supported by IBB to A.U.B./U.S. and the SonnenfeldStiftung, which sponsored technical equipment for A.U.B. and U.S. The authors thank Kimberly Mason for editing the manuscript.

a

Chromosome (5q22) Human Chromosome (9q31.1) Mouse Chromosome B1;4) Rat Chromosome 8 (8q13) Human Chromosome (19p13.2) Mouse Chromosome Rat

NP_055654.2 NP_808332.3 NP_853665.1 NP_079164.1 NP_859009.2

NP_001005881 19

NP_001164106.1

References

9 (9)

NP_659184

[1] A.U. Brauer, R. Nitsch, Plasticity-related genes (PRGs/LRPs): a brain-specific class of lysophospholipid-modifying proteins, Biochim. Biophys. Acta 1781 (2008) 595–600. [2] A.U. Brauer, N.E. Savaskan, H. Kuhn, S. Prehn, O. Ninnemann, R. Nitsch, A new phospholipid phosphatase, PRG-1, is involved in axon growth and regenerative sprouting, Nat. Neurosci. 6 (2003) 572–578. [3] N.E. Savaskan, A.U. Brauer, R. Nitsch, Molecular cloning and expression regulation of PRG-3, a new member of the plasticity-related gene family, Eur. J. Neurosci. 19 (2004) 212–220. [4] T. Broggini, R. Nitsch, N.E. Savaskan, Plasticity-related gene 5 (PRG5) induces filopodia and neurite growth and impedes lysophosphatidic acid- and nogoA-mediated axonal retraction, Mol. Biol. Cell 21 (2010) 521–537. [5] D.N. Brindley, D.W. Waggoner, Mammalian lipid phosphate phosphohydrolases, J. Biol. Chem. 273 (1998) 24281–24284. [6] Y.J. Sigal, M.I. McDermott, A.J. Morris, Integral membrane lipid phosphatases/ phosphotransferases: common structure and diverse functions, Biochem. J. 387 (2005) 281–293. [7] S. Willi-Monnerat, E. Migliavacca, D. Surdez, M. Delorenzi, R. Luthi-Carter, A.V. Terskikh, Comprehensive spatiotemporal transcriptomic analyses of the ganglionic eminences demonstrate the uniqueness of its caudal subdivision, Mol. Cell. Neurosci. 37 (2008) 845–856. [8] T. Trimbuch, P. Beed, J. Vogt, S. Schuchmann, Synaptic PRG-1 modulates excitatory transmission via lipid phosphate-mediated signaling, Cell 138 (2009) 1222–1235. [9] H. Tokumitsu, N. Hatano, M. Tsuchiya, S. Yurimoto, T. Fujimoto, N. Ohara, R. Kobayashi, H. Sakagami, Identification and characterization of PRG-1 as a neuronal calmodulin-binding protein, Biochem. J. 431 (2010) 81–91. [10] W.Z. Wang, Z. Molnar, Dynamic pattern of mRNA expression of plasticity-related gene-3 (PRG-3) in the mouse cerebral cortex during development, Brain Res. Bull. 66 (2005) 454–460. [11] L. Sun, S. Gu, Y. Sun, D. Zheng, Q. Wu, X. Li, J. Dai, C. Ji, Y. Xie, Y. Mao, Cloning and characterization of a novel human phosphatidic acid phosphatase type 2, PAP2d, with two different transcripts PAP2d_v1 and PAP2d_v2, Mol. Cell. Biochem. 272 (2005) 91–96. [12] B. Geist, B. Vorwerk, P. Coiro, O. Ninnemann, R. Nitsch, PRG-1 transcriptional regulation independent from Nex1/Math2-mediated activation, Cell Mol. Life Sci. 69 (2012) 651–661. [13] S. Impey, S.R. McCorkle, H. Cha-Molstad, J.M. Dwyer, G.S. Yochum, J.M. Boss, S. McWeeney, J.J. Dunn, G. Mandel, R.H. Goodman, Defining the CREB regulon: a genome-wide analysis of transcription factor regulatory regions, Cell 119 (2004) 1041–1054. [14] X. Zhang, D.T. Odom, S.H. Koo, M.D. Conkright, G. Canettieri, J. Best, H. Chen, R. Jenner, E. Herbolsheimer, E. Jacobsen, S. Kadam, J.R. Ecker, B. Emerson, J.B. Hogenesch, T. Unterman, R.A. Young, M. Montminy, Genome-wide analysis of cAMP-response element binding protein occupancy, phosphorylation, and target gene activation in human tissues, Proc. Natl. Acad. Sci. U. S. A. 102 (2005) 4459–4464. [15] M. Yamada, Y. Shida, K. Takahashi, T. Tanioka, Y. Nakano, T. Tobe, Prg1 is regulated by the basic helix-loop-helix transcription factor Math2, J. Neurochem. 106 (2008) 2375–2384. [16] H. Yaguchi, F. Okumura, H. Takahashi, T. Kano, H. Kameda, M. Uchigashima, S. Tanaka, M. Watanabe, H. Sasaki, S. Hatakeyama, TRIM67 protein negatively regulates Ras activity through degradation of 80K-H and induces neuritogenesis, J. Biol. Chem. 287 (2012) 12050–12059. [17] P. Villalonga, C. Lopez-Alcala, M. Bosch, A. Chiloeches, N. Rocamora, J. Gil, R. Marais, C.J. Marshall, O. Bachs, N. Agell, Calmodulin binds to K-Ras, but not to H- or N-Ras, and modulates its downstream signaling, Mol. Cell. Biol. 21 (2001) 7345–7354.

Chromosome 2 (2q41) Human Chromosome 1 (1p21.3) Mouse Chromosome 3 (3G2)

NP_001101190.1 NP_001010861.1 NP_083701.2

http://www.ncbi.nlm.nih.gov.

5. PRG/LPPR and cancer Although the role of a putative target of PRG1/LPPR4, lysophosphatidic acid (LPA), in cancer is generally accepted, the involvement of PRGs/LPPRs in cancerogenesis or treatment is less clear. Concomitant with the pro-cancerogenous role of LPA [39,40], PRG1/ LPPR4 downregulation was suggested to be involved in the leukemogenic process, because it was lower in peripheral blood-derived B-cells in response to the major oncogene TaxBLV [41]. However, it remains to be elucidated whether PRG/LPPR expression in lymphocyctes is just a consequence of cancerous degeneration (see also above). Nevertheless, some malignomas deriving from neuronal crest cells do associate with changes in PRG/LPPR levels. In a case involving a second recurrence of human adrenal cell carcinoma, PRG3/LPPR1 was found underexpressed [42]. It would be interesting to investigate whether PRG3/LPPR1 is involved in tumor suppression of adrenal carcinomas. On the other hand, increased PRG4/LPPR2 expression was linked to drug resistance in human melanoma cell lines [43]. Thus, there are indications that PRGs/LPPRs may play a role beyond the central nervous system, in particular in the control of malign degeneration. The exact relationship of PRGs/LPPRs and tumor progression will be a matter for future studies. 6. Open questions Despite the substantial increase in knowledge in the relatively new field of PRG/LPPR research over the last several years, there still remain a number of questions, partially addressed already. These concern, for instance, the differential (sub)cellular distribution of all PRG/LPPR subunits on a spatio–temporal level. Distribution patterns combined with the impact on function, e.g. if synaptic effects are restricted to hippocampal structures or constitute a general

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