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Clustered protocadherins (cPcdhs) constitute the largest subgroup of the cadherin superfamily, and in mammals are grouped into clusters of α-, β-, and γ-types. Tens of tandemly arranged paralogous Pcdh genes of the Pcdh clusters generate a substantial diversity of receptor isoforms. cPcdhs are known to have important roles in neuronal development, and genetic alterations of cPcdhs have been found to be associated with several neurological diseases. Here, we present a first characterization of cPcdhs in Xenopus tropicalis We determined and annotated all cPcdh isoforms, revealing that they are present in a single chromosomal locus. We validated a total of 96 isoforms, which we show are organized in three distinct clusters. The X. tropicalis cPcdh locus is composed of one α- and two distinct γ-Pcdh clusters (pcdh-γ1 and pcdh-γ2). Bioinformatics analyses assisted by genomic BAC clone sequencing showed that the X. tropicalis α- and γ-Pcdhs are conserved at the cluster level, but, unlike mammals, X. tropicalis does not contain a β-Pcdh cluster. In contrast, the number of γ-Pcdh isoforms has expanded, possibly due to lineage-specific gene duplications. Interestingly, the number of X. tropicalis α-Pcdhs is identical between X. tropicalis and mouse. Moreover, we find highly conserved as well as novel promoter elements potentially involved in regulating the cluster-specific expression of cPcdh isoforms. This study provides important information for the understanding of the evolutionary history of cPcdh genes and future mechanistic studies. It provides an annotated X. tropicalis cPcdh genomic map and a first molecular characterization essential for functional and comparative studies.
Figure 1. Genomic organization of the X. tropicalis cPcdhs. (A) Representative diagram showing X. tropicalis cPcdhs gene models. Longer and thinner rectangles denote variable exons, shorter and thicker rectangles denote constant exons. Green: pcdh-δ, blue: pcdh-α, purple: pcdh-γ1, red: pcdh-γ2. Black arrows above the gene models denote the orientation of the clusters. Gray bars below the gene models correspond to the sequenced BAC clones. (B) Genomic map of X. tropicalis cPcdhs loci based on genome build 9.0.
Figure 2. Phylogenetic analysis of cPcdhs at the cluster level. The tree was generated using ML and is based on the multiple sequence alignment of the constant domains of different Pcdh clusters. % Bootstrap values of major nodes are shown. Ac, anole; Cm, elephant shark; Dr, zebrafish; Gg, chicken; Lm, coelacanth; Mm, mouse; Xt, X. tropicalis.
Figure 3. Phylogenetic relationships of mouse and X. tropicalis cPcdhs. The tree was generated with ML using the multiple sequence alignments of EC2âEC3 of mouse and X. tropicalis cPcdh isoforms.
Figure 4. (A) Schematic representation of the conserved sequence motifs of X. tropicalis cPcdh promoters. Dotted arrows, filled arrows, and open arrows represent the genomic position of conserved motifs of (leftâright) pcdh-α, pcdh-γ1 and pcdh-γ2. (B) CSE of mouse α-Pcdhs and X. tropicalis pcdh-α. (C) CSE of mouse γ-Pcdhs and X. tropicalis pcdh-γ1 and pcdh-γ2 1â13. (D) The newly identified sequence motif present in the promoters of pcdh-γ2 15â36. The asterisks indicate the âCGCT box.â
Figure 5. Expression of X. tropicalis cPcdhs. (A) X. tropicalis cPcdh expression over 19 different developmental stages in FPKM units (reanalyzed from Tan et al. 2013). (BâE) X. tropicalis cPcdh RNA in situ hybridization sense and antisense probes. (FâI) Spatial expression patterns of X. tropicalis cPcdhs as detected by RNA in situ hybridization. (BâI) mRNA in situ hybridization results of the X. tropicalis cPcdhs. The pan-gamma riboprobe targets the constant exons of pcdh-γ1, and most likely recognizes the pcdh-γ2 cluster constant exons as well because of high sequence similarity of the constant exons of the two γ clusters (73.89% sequence identity). The gamma1 and gamma2 riboprobes recognize the 3â²UTR regions of pcdh-γ1 and pcdh-γ2 clusters, respectively, and the alpha riboprobe recognizes the constant exons of the pcdh-α cluster. (BâE) Sense and antisense probes. (FâI) Additional images from the antisense probes.
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