期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 105, 期 18, 页码 6714-6719出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0707057105
关键词
sonic hedgehog; Wnt; cilia; cell migration
资金
- MRC [MC_U117560541, G117/506] Funding Source: UKRI
- Medical Research Council [MC_U117560541, G117/506] Funding Source: researchfish
- FIC NIH HHS [R21TW06761-01, R21 TW006761] Funding Source: Medline
- Medical Research Council [G117/506, G0801843, MC_U117560541] Funding Source: Medline
- NICHD NIH HHS [R01 HD39372, U01 HD039372] Funding Source: Medline
- NIDCR NIH HHS [P50 DE 016215-01, R01 DE015210, P50 DE016215] Funding Source: Medline
- NIEHS NIH HHS [P01 ES011253, P01 ES11253] Funding Source: Medline
- Wellcome Trust Funding Source: Medline
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.
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