title: Upregulation of the Nr2f1-A830082K12Rik gene pair in murine neural crest cells results in a complex phenotype reminiscent of Waardenburg syndrome type 4.
abstract: Waardenburg syndrome is a neurocristopathy characterized by a combination of skin and hair depigmentation, and inner ear defects. In the type 4 form, these defects show comorbidity with Hirschsprung disease, a disorder marked by an absence of neural ganglia in the distal colon, triggering functional intestinal obstruction. Here, we report that the Spot mouse line - obtained through an insertional mutagenesis screen for genes involved in neural crest cell (NCC) development - is a model for Waardenburg syndrome type 4. We found that the Spot insertional mutation causes overexpression of an overlapping gene pair composed of the transcription-factor-encoding Nr2f1 and the antisense long non-coding RNA A830082K12Rik in NCCs through a mechanism involving relief of repression of these genes. Consistent with the previously described role of Nr2f1 in promoting gliogenesis in the central nervous system, we further found that NCC-derived progenitors of the enteric nervous system fail to fully colonize Spot embryonic guts owing to their premature differentiation in glial cells. Taken together, our data thus identify silencer elements of the Nr2f1-A830082K12Rik gene pair as new candidate loci for Waardenburg syndrome type 4.
authors: Molecular Genetics of Development Laboratory, Department of Biological Sciences and BioMed Research Center, University of Quebec at Montreal (UQAM), Montreal, H2X 3Y7, Canada.
authors: Karl-F
authors: KF
authors: Bergeron
authors: Molecular Genetics of Development Laboratory, Department of Biological Sciences and BioMed Research Center, University of Quebec at Montreal (UQAM), Montreal, H2X 3Y7, Canada.
authors: Chloé M A
authors: CM
authors: Nguyen
authors: Molecular Genetics of Development Laboratory, Department of Biological Sciences and BioMed Research Center, University of Quebec at Montreal (UQAM), Montreal, H2X 3Y7, Canada.
authors: Tatiana
authors: T
authors: Cardinal
authors: Molecular Genetics of Development Laboratory, Department of Biological Sciences and BioMed Research Center, University of Quebec at Montreal (UQAM), Montreal, H2X 3Y7, Canada.
authors: Baptiste
authors: B
authors: Charrier
authors: Veterinary Genetics Laboratory, Faculty of Veterinary Medicine, University of Montreal, St-Hyacinthe, J2S 7C6, Canada.
authors: David W
authors: DW
authors: Silversides
authors: Molecular Genetics of Development Laboratory, Department of Biological Sciences and BioMed Research Center, University of Quebec at Montreal (UQAM), Montreal, H2X 3Y7, Canada pilon.nicolas@uqam.ca.
authors: Nicolas
authors: 0000-0003-3641-0776
authors: N
authors: Pilon
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D051838:COUP Transcription Factor I / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics; D004710:Endolymph / Q000378:metabolism; D017615:Enteric Nervous System / Q000473:pathology; D006627:Hirschsprung Disease / Q000235:genetics*; D008544:Melanocytes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D016254:Mutagenesis, Insertional; D009432:Neural Crest / Q000378:metabolism* / Q000473:pathology*; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D010858:Pigmentation / Q000235:genetics; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D019076:Transgenes; D015854:Up-Regulation / Q000235:genetics*; D014849:Waardenburg Syndrome / Q000235:genetics*
chemical_list: C000625217:A830082K12Rik non-coding RNA, mouse; D051838:COUP Transcription Factor I; C497590:Nr2f1 protein, mouse; D062085:RNA, Long Noncoding
keywords: Enteric nervous system; Hirschsprung disease; Melanocytes; Mouse model; Neural crest cells; Waardenburg syndrome