Inhibition of neural crest migration underlies craniofacial dysmorphology and Hirschsprung's disease in Bardet-Biedl syndrome.
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.
Tobin
Jonathan L
JL
Molecular Medicine Unit, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, United Kingdom.
Di Franco
Matt
M
Eichers
Erica
E
May-Simera
Helen
H
Garcia
Monica
M
Yan
Jiong
J
Quinlan
Robyn
R
Justice
Monica J
MJ
Hennekam
Raoul C
RC
Briscoe
James
J
Tada
Masazumi
M
Mayor
Roberto
R
Burns
Alan J
AJ
Lupski
James R
JR
Hammond
Peter
P
Beales
Philip L
PL
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
D053823:Hedgehog Proteins; D051153:Wnt Proteins; D029961:Zebrafish Proteins