title: Inhibition of neural crest migration underlies craniofacial dysmorphology and Hirschsprung's disease in Bardet-Biedl syndrome.
abstract: Facial recognition is central to the diagnosis of many syndromes, and craniofacial patterns may reflect common etiologies. In the pleiotropic Bardet-Biedl syndrome (BBS), a primary ciliopathy with intraflagellar transport dysfunction, patients have a characteristic facial "gestalt" that dysmorphologists have found difficult to characterize. Here, we use dense surface modeling (DSM) to reveal that BBS patients and mouse mutants have mid-facial defects involving homologous neural crest-derived structures shared by zebrafish morphants. These defects of the craniofacial (CF) skeleton arise from aberrant cranial neural crest cell (NCC) migration. These effects are not confined to the craniofacial region, but vagal-derived NCCs fail to populate the enteric nervous system, culminating in disordered gut motility. Furthermore, morphants display hallmarks of disrupted Sonic Hedgehog (Shh) signaling from which NCCs take positional cues. We propose a model whereby Bbs proteins modulate NCC migration, contributing to craniofacial morphogenesis and development of the enteric nervous system. These migration defects also explain the association of Hirschsprung's disease (HD) with BBS. Moreover, this is a previously undescribed method of using characterization of facial dysmorphology as a basis for investigating the pathomechanism of CF development in dysmorphic syndromes.
authors.affiliation: Molecular Medicine Unit, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, United Kingdom.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Tobin
authors.forename: Matt
authors.initials: M
authors.lastname: Di Franco
authors.forename: Erica
authors.initials: E
authors.lastname: Eichers
authors.forename: Helen
authors.initials: H
authors.lastname: May-Simera
authors.forename: Monica
authors.initials: M
authors.lastname: Garcia
authors.forename: Jiong
authors.initials: J
authors.lastname: Yan
authors.forename: Robyn
authors.initials: R
authors.lastname: Quinlan
authors.forename: Monica J
authors.initials: MJ
authors.lastname: Justice
authors.forename: Raoul C
authors.initials: RC
authors.lastname: Hennekam
authors.forename: James
authors.initials: J
authors.lastname: Briscoe
authors.forename: Masazumi
authors.initials: M
authors.lastname: Tada
authors.forename: Roberto
authors.initials: R
authors.lastname: Mayor
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Burns
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.forename: Peter
authors.initials: P
authors.lastname: Hammond
authors.forename: Philip L
authors.initials: PL
authors.lastname: Beales
mesh_terms: D000818:Animals; D020788:Bardet-Biedl Syndrome / Q000150:complications* / Q000503:physiopathology; D002465:Cell Movement; D002923:Cilia / Q000473:pathology; D019465:Craniofacial Abnormalities / Q000150:complications* / Q000503:physiopathology; D017615:Enteric Nervous System / Q000503:physiopathology; D005769:Gastrointestinal Motility; D053823:Hedgehog Proteins / Q000378:metabolism; D006627:Hirschsprung Disease / Q000150:complications* / Q000503:physiopathology; D006801:Humans; D021621:Imaging, Three-Dimensional; D051379:Mice; D009154:Mutation / Q000235:genetics; D041681:NIH 3T3 Cells; D009432:Neural Crest / Q000473:pathology*; D010641:Phenotype; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism; D015027:Zebrafish / Q000002:abnormalities; D029961:Zebrafish Proteins / Q000378:metabolism
chemical_list: D053823:Hedgehog Proteins; D051153:Wnt Proteins; D029961:Zebrafish Proteins