Clustered protocadherins

Abstract

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...

Characterization and Identification of Differentially Expressed Genes Involved in Thermal Adaptation of the Hong Kong Oyster Crassostrea hongkongensis by Digital Gene Expression Profiling

“…Additional evidence reflective of changes in cytoskeletal organization in the present study comes from the decreased expression of protocadherins Tenascin X, and an extracellular matrix protein, plays a crucial architectural function by modulating cell adhesion (Bristow et al, 2005). Protocadherins constitute the largest subfamily of the cadherin superfamily of cell-adhesion molecules (Chen and Maniatis, 2013). Our findings strongly suggest extensive cytoskeletal reorganization in the oyster in response to thermal stress.…”

Regulation of the Protocadherin Celsr3 Gene and Its Role in Globus Pallidus Development and Connectivity

“…The Pcdh genes constitute a large subfamily of the cadherin superfamily that are expressed mainly in the central nervous system in a cell-or tissue-specific or developmental-stage-specific manner (49,50). In particular, the clustered Pcdh genes are organized into variable and constant regions and generate enormous neural diversity by stochastic promoter choice combined with alternative pre-mRNA splicing (51)(52)(53).…”

Fruit Flies in Biomedical Research

“…Interestingly, however, in mammals a different class of transmembrane receptors called Protocadherins (Pcdhs) has the potential to generate a large number (.12,000) of different isoforms that provide neuronal specificity (Chen and Maniatis 2013). Although the mechanisms of generating diverse isoforms are different between Dscam1 and Pcdhs (alternative RNA splicing vs. alternative promoter usage and formation of heteromultimers), many parallels can be drawn between the two examples.…”