Changes in subcellular distribution of protocadherin gamma proteins accompany maturation of spinal neurons

Kallenbach, Sacha; Khantane, Sabrina; Carroll, Patrick; Gayet, Odile; Alonso, Serge; Henderson, Chris; Dudley, Keith

doi:10.1002/jnr.10618

Cited by 29 publications

(38 citation statements)

References 18 publications

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“…Except for DDIT4L, whosesilencing had beenidentified in melanomas[27], silencing of these genes was a novel finding in any types of cancers. Although FERD3L and PCDHGC4 were not expressed in the adrenal medulla, their expression in embryonal tissues and important roles in neuronal development have been reported [23, 28, 29]. This supported our hypothesis that CIMP affects various nonpromoter and promoter CGIs, that its presence is sensitively detected by methylation of nonpromoter CGIs and that its biological effects are exerted by methylation of promoter CGIs of various genes.…”

Section: Discussionsupporting

confidence: 76%

See 1 more Smart Citation

Identification of Genes Targeted by CpG Island Methylator Phenotype in Neuroblastomas, and Their Possible Integrative Involvement in Poor Prognosis

Abe

Watanabe²,

McDonell³

et al. 2008

Oncology

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Background/Aims: CpG island (CGI) methylator phenotype (CIMP) is strongly associated with poor prognosis in neuroblastomas (NBLs; hazard ratios 7–22). Methylation of nonpromoter CGIs is useful to detect the presence of the CIMP, while the poor prognosis is considered to be caused by gene silencing due to promoter methylation. Here, promoter CGIs targeted by the CIMP were searched for. Methods: A genome-wide screening was performed by methylation-sensitive representational difference analysis of CIMP(+) and CIMP(–) NBLs. Results: Promoter CGIs of 9 genes were methylated in CIMP(+) NBL cell lines and caused silencing of their downstream genes. On analysis of 90 clinical specimens, CYP26C1,FERD3L (N-TWIST), CRYBA2 and PCDHGC4 were methylated at significantly higher incidences in CIMP(+) NBLs than CIMP(–) NBLs, while the difference was unclear for NPY, SPAG6, DDIT4L, CHR3SYT and C6Orf141. Methylation of CYP26C1 and FERD3L was significantly associated with poor prognosis, but weaker than the presence of the CIMP. Treatment of an NBL cell line with a demethylating agent caused demethylation of multiple promoter CGIs, and enhanced 13-cis-retinoic acid-induced neuronal differentiation. Conclusion: Our results indicate that the CIMP causes poor prognosis of NBLs by inducing methylation of multiple promoter CGIs with various incidences.

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Section: Discussionsupporting

confidence: 76%

“…PCDHGC4 is a member of the protocadherin- γ gene family, which is deeply involved in neuronal maturation and brain development [28, 29]. One of the protocadherin- γ family genes, PCDHGA11 , is reported to be silenced in astrocytomas [30].…”

Section: Discussionmentioning

confidence: 99%

Identification of Genes Targeted by CpG Island Methylator Phenotype in Neuroblastomas, and Their Possible Integrative Involvement in Poor Prognosis

Abe

Watanabe²,

McDonell³

et al. 2008

Oncology

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“…All three classes of clustered Pcdh proteins are detected throughout the neuronal soma, dendrites and axons, and are observed in synapses and growth cones (Kohmura et al, 1998;Wang et al, 2002b;Kallenbach et al, 2003;Phillips et al, 2003;Junghans et al, 2008). The presence of Pcdh proteins at the synapse led to speculation that these cell-surface proteins may provide a synaptic adhesive code for specifying neuronal connections (Shapiro and Colman, 1999;Takeichi, 2007).…”

Section: Homophilic Interactions and Intracellular Signalingmentioning

confidence: 99%

Clustered protocadherins

Chen

Maniatis²

2013

Development

169

176

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The majority of vertebrate protocadherin (Pcdh) genes are clustered in a single genomic locus, and this remarkable genomic organization is highly conserved from teleosts to humans. These clustered Pcdhs are differentially expressed in individual neurons, they engage in homophilic trans-interactions as multimers and they are required for diverse neurodevelopmental processes, including neurite self-avoidance. Here, we provide a concise overview of the molecular and cellular biology of clustered Pcdhs, highlighting how they generate single cell diversity in the vertebrate nervous system and how such diversity may be used in neural circuit assembly.Key words: CTCF, Cohesin, Promoter choice, Single cell diversity, Homophilic interaction, Self-avoidance Introduction Protocadherins (Pcdhs), which are predominantly expressed in the nervous system, constitute the largest subfamily of the cadherin superfamily of cell-adhesion molecules. The founding members of the Pcdh gene family were discovered by Suzuki and co-workers in an effort to isolate novel cadherin repeat-containing genes (Sano et al., 1993). Distinct Pcdh members were subsequently cloned, and these included a set of eight cDNAs encoding cadherin-related neuronal receptors (CNRs) (Kohmura et al., 1998). A striking characteristic of the corresponding CNR mRNAs is that their 5Ј ends are distinct, whereas their 3Ј ends are all identical, suggesting that they are generated by alternative pre-mRNA splicing. Characterization of the human genomic DNA encoding the CNR mRNAs revealed that they are encoded in a large Pcdh gene cluster designated α (Pcdha), which is located immediately upstream of two additional Pcdh gene clusters designated β (Pcdhb) and γ (Pcdhg) (Wu and Maniatis, 1999). Remarkably, the genomic organization of the Pcdh gene clusters resembles that of the immunoglobulin and T-cell receptor genes, both of which generate enormous diversity in the immune system through a mechanism that Development 140, 3297-3302 (2013) DEVELOPMENT 3298 involves somatic cell DNA rearrangement. Subsequent studies confirmed the possibility that the clustered Pcdhs serve as a source of molecular diversity in the nervous system, albeit through a different mechanism. The enormous cell surface diversity resulting from the combinatorial expression of Pcdh isoforms, together with the extraordinary specificity afforded by their homophilic interactions, have led to the speculation that clustered Pcdhs are functional counterparts of the Drosophila Dscam1 proteins, which play a central role in neural circuit assembly in the invertebrate nervous system (Zipursky and Sanes, 2010). Indeed, recent studies have demonstrated that the Pcdhg gene cluster is required for neurite self-avoidance in the mouse, in a manner similar to that of the Dscam1 gene in the fly (Lefebvre et al., 2012). Thus, it appears that clustered Pcdhs may function as molecular barcodes for selfrecognition by individual neurons in the vertebrate nervous system. Here, we briefly review studies that led to this hypothesis...

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“…Protocadherin ␣ and ␥ transcripts and proteins are expressed in overlapping but distinct patterns in the brain, and individual neurons have been shown to express multiple Pcdh␣ proteins (Kohmura et al 1998;Tasic et al 2002;Wang et al 2002b). These results suggest a new model in which Pcdh proteins are required for neuronal maturation and synaptic modification rather than synaptogenesis (Wang et al 2002b;Kallenbach et al 2003;Phillips et al 2003). In this model, protocadherin cluster proteins are not structural components of synapses, but serve to identify and modify an enormous number of neuronal and synaptic subpopulations in the developing and adult brain (Phillips et al 2003).…”

mentioning

confidence: 91%

Gene Conversion and the Evolution of Protocadherin Gene Cluster Diversity

Noonan¹,

Grimwood²,

Schmutz³

et al. 2004

Genome Res.

102

125

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The synaptic cell adhesion molecules encoded by the protocadherin gene cluster are hypothesized to provide a molecular code involved in the generation of synaptic complexity in the developing brain. Variation in copy number and sequence content of protocadherin cluster genes among vertebrate species could reflect adaptive differences in protocadherin function. We have completed an analysis of zebrafish protocadherin cluster genes. Zebrafish have two unlinked protocadherin clusters, DrPcdh1 and DrPcdh2. Like mammalian protocadherin clusters, DrPcdh1 has both ␣ and ␥ variable and constant region exons. A consensus protocadherin promoter motif sequence identified in mammals is also conserved in zebrafish. Few orthologous relationships, however, are apparent between zebrafish and mammalian protocadherin proteins. Here we show that protocadherin cluster genes in human, mouse, rat, and zebrafish are subject to striking gene conversion events. These events are restricted to regions of the coding sequence, particularly the coding sequences of ectodomain 6 and the cytoplasmic domain. Diversity among paralogs is restricted to particular ectodomains that are excluded from conversion events. Conversion events are also strongly correlated with an increase in third-position GC content. We propose that the combination of lineage-specific duplication, restricted gene conversion, and adaptive variation in diversified ectodomains drives vertebrate protocadherin cluster evolution.

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Changes in subcellular distribution of protocadherin gamma proteins accompany maturation of spinal neurons

Cited by 29 publications

References 18 publications

Identification of Genes Targeted by CpG Island Methylator Phenotype in Neuroblastomas, and Their Possible Integrative Involvement in Poor Prognosis

Identification of Genes Targeted by CpG Island Methylator Phenotype in Neuroblastomas, and Their Possible Integrative Involvement in Poor Prognosis

Clustered protocadherins

Gene Conversion and the Evolution of Protocadherin Gene Cluster Diversity

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