Planar cell polarity genes, Celsr1-3, in neural development.
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ABSTRACT:
SUBMITTER: Feng J
PROVIDER: S-EPMC5560321 | biostudies-other | 2012 Jun
REPOSITORIES: biostudies-other
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Project description:Neural tube defects (NTDs) are considered to be a complex genetic disorder, although the identity of the genetic factors remains largely unknown. Mouse model studies suggest a multifactorial oligogenic pattern of inheritance for NTDs, yet evidence from published human studies is surprisingly absent. In the present study, targeted next-generation sequencing was performed to screen for DNA variants in the entire coding regions and intron-exon boundaries of targeted genes using DNA samples from 510 NTD cases. These candidate genes were PCP genes, including VANGL1, VANGL2, CELSR1, SCRIB, DVL2, DVL3 and PTK7. Candidate variants were validated using Sanger sequencing. A total of 397 single nucleotide variants(SNVs) were identified with a mean depth of approximately 570×. Of these identified SNVs, 74 were predicted to affect protein function and had a minor allele frequency of <0.01 or unknown. Among these 74 missense SNVs, 10 were identified from six NTD cases that carried two mutated genes. Of the six NTD cases, three spina bifida cases and one anencephaly case carried digenic variants in the CELSR1 and SCRIB gene; one anencephaly case carried variants in the CELSR1 and DVL3 gene; and one spina bifida case carried variants in the PTK7 and SCRIB genes. Three cases that parental samples were available were confirmed to be compound heterozygous. None of the digenic variants were found in the 1000 genome database. The findings imply that genetic variation might interact in a digenic fashion to generate the visible NTD phenotypes and emphasize the importance of these genetic interactions in the development of NTDs in humans.
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Project description:The ability to stop producing or replacing cells at the appropriate time is essential, as uncontrolled growth can lead to loss of function and even cancer. Tightly regulated mechanisms coordinate the growth of stem cell progeny with the patterning needs of the host organism. Despite the importance of proper termination during regeneration, cell turnover, and embryonic development, very little is known about how tissues determine when patterning is complete during these processes. Using planarian flatworms, we show that the planar cell polarity (PCP) pathway is required to stop the growth of neural tissue. Although traditionally studied as regulators of tissue polarity, we found that loss of the PCP genes Vangl2, DAAM1, and ROCK by RNA interference (individually or together) resulted in supernumerary eyes and excess optical neurons in intact planarians, while regenerating planarians had continued hyperplasia throughout the nervous system long after controls ceased new growth. This failure to terminate growth suggests that neural tissues use PCP as a readout of patterning, highlighting a potential role for intact PCP as a signal to stem and progenitor cells to halt neuronal growth when patterning is finished. Moreover, we found this mechanism to be conserved in vertebrates. Loss of Vangl2 during normal development, as well as during Xenopus tadpole tail regeneration, also leads to the production of excess neural tissue. This evolutionarily conserved function of PCP represents a tractable new approach for controlling the growth of nerves.
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Project description:Neural tube defects (NTDs) are among the commonest and most severe forms of developmental defect, characterized by disruption of the early embryonic events of central nervous system formation. NTDs have long been known to exhibit a strong genetic dependence, yet the identity of the genetic determinants remains largely undiscovered. Initiation of neural tube closure is disrupted in mice homozygous for mutations in planar cell polarity (PCP) pathway genes, providing a strong link between NTDs and PCP signaling. Recently, missense gene variants have been identified in PCP genes in humans with NTDs, although the range of phenotypes is greater than in the mouse mutants. In addition, the sequence variants detected in affected humans are heterozygous, and can often be detected in unaffected individuals. It has been suggested that interactions between multiple heterozygous gene mutations cause the NTDs in humans. To determine the phenotypes produced in double heterozygotes, we bred mice with all three pairwise combinations of Vangl2(Lp), Scrib(Crc) and Celsr1(Crsh) mutations, the most intensively studied PCP mutants. The majority of double-mutant embryos had open NTDs, with the range of phenotypes including anencephaly and spina bifida, therefore reflecting the defects observed in humans. Strikingly, even on a uniform genetic background, variability in the penetrance and severity of the mutant phenotypes was observed between the different double-heterozygote combinations. Phenotypically, Celsr1(Crsh);Vangl2(Lp);Scrib(Crc) triply heterozygous mutants were no more severe than doubly heterozygous or singly homozygous mutants. We propose that some of the variation between double-mutant phenotypes could be attributed to the nature of the protein disruption in each allele: whereas Scrib(Crc) is a null mutant and produces no Scrib protein, Celsr1(Crsh) and Vangl2(Lp) homozygotes both express mutant proteins, consistent with dominant effects. The variable outcomes of these genetic interactions are of direct relevance to human patients and emphasize the importance of performing comprehensive genetic screens in humans.
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Project description:Planar cell polarity (PCP) is an essential feature of animal tissues, whereby distinct polarity is established within the plane of a cell sheet. Tissue-wide establishment of PCP is driven by multiple global cues, including gradients of gene expression, gradients of secreted WNT ligands and anisotropic tissue strain. These cues guide the dynamic, subcellular enrichment of PCP proteins, which can self-assemble into mutually exclusive complexes at opposite sides of a cell. Endocytosis, endosomal trafficking and degradation dynamics of PCP components further regulate planar tissue patterning. This polarization propagates throughout the whole tissue, providing a polarity axis that governs collective morphogenetic events such as the orientation of subcellular structures and cell rearrangements. Reflecting the necessity of polarized cellular behaviours for proper development and function of diverse organs, defects in PCP have been implicated in human pathologies, most notably in severe birth defects.
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Project description:Extensive studies that have sought causative mutation(s) for neural tube defects (NTDs) have yielded limited positive findings to date. One possible reason for this is that many studies have been confined to analyses of germline mutations and so may have missed other, non-germline mutations in NTD cases. We hypothesize that somatic mutations of planar polarity pathway (PCP) genes may play a role in the development of NTDs. Torrent™ Personal Genome Machine™ (PGM) sequencing was designed for selected PCP genes in paired DNA samples extracted from the tissues of lesion sites and umbilical cord from 48 cases. Sanger sequencing was used to validate the detected mutations. The source and distribution of the validated mutations in tissues from different germ layers were investigated. Subcellular location, western blotting, and luciferase assays were performed to better understand the effects of the mutations on protein localization, protein level, and pathway signaling. ix somatic mutations were identified and validated, which showed diverse distributions in different tissues. Three somatic mutations were novel/rare: CELSR1 p.Gln2125His, FZD6 p.Gln88Glu, and VANGL1 p.Arg374His. FZD6 p.Gln88Glu caused mislocalization of its protein from the cytoplasm to the nucleus, and disrupted the colocalization of CELSR1 and FZD6. This mutation affected non-canonical WNT signaling in luciferase assays. VANGL1 p.Arg374His impaired the co-localization of CELSR1 and VANGL1, increased the protein levels of VANGL1, and influenced cell migration. In all, 7/48 (14.5%) of the studied NTD cases contained somatic PCP mutations. Somatic mutations in PCP genes (e.g., FZD6 and VANGL1) are associated with human NTDs, and they may occur in different stages and regions during embryonic development, resulting in a varied distribution in fetal tissues/organs.
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