Abstract
The Hedgehog (Hh) signaling pathway mediates multiple spatiotemporally-specific aspects of brain and face development. Genetic and chemical disruptions of the pathway are known to result in an array of structural malformations, including holoprosencephaly (HPE), clefts of the lip with or without cleft palate (CL/P), and clefts of the secondary palate only (CPO). Here, we examined patterns of dysmorphology caused by acute, stage-specific Hh signaling inhibition. Timed-pregnant wildtype C57BL/6J mice were administered a single dose of the potent pathway antagonist vismodegib at discrete time points between gestational day (GD) 7.0 and 10.0, an interval approximately corresponding to the 15th to 24th days of human gestation. The resultant pattern of facial and brain dysmorphology was dependent upon stage of exposure. Insult between GD7.0 and GD8.25 resulted in HPE, with peak incidence following exposure at GD7.5. Unilateral clefts of the lip extending into the primary palate were also observed, with peak incidence following exposure at GD8.875. Insult between GD9.0 and GD10.0 resulted in CPO and forelimb abnormalities. We have previously demonstrated that Hh antagonist-induced cleft lip results from deficiency of the medial nasal process and show here that CPO is associated with reduced growth of the maxillary-derived palatal shelves. By defining the critical periods for the induction of HPE, CL/P, and CPO with fine temporal resolution, these results provide a mechanism by which Hh pathway disruption can result in “non-syndromic” orofacial clefting, or HPE with or without co-occurring clefts. This study also establishes a novel and tractable mouse model of human craniofacial malformations using a single dose of a commercially available and pathway-specific drug.
Highlights
Orofacial clefts (OFCs), including cleft lip with or without cleft palate (CL/P) and cleft palate only (CPO), are commonly occurring human birth defects that cause significant morbidity and require extensive medical intervention
Inter- and intra-litter penetrance is shown in S2 Fig. Less frequently observed phenotypic variants of HPE, CL/P, and CPO resulting from each exposure paradigm are shown in S3 Fig. The majority of fetuses exposed to vismodegib between the critical periods for HPE and OFCs exhibited grossly normal craniofacial morphology (Fig. 1C,C’)
Perturbation of the Hh signaling pathway has been associated with HPE, CL/P and CPO in both animal models and in clinical populations
Summary
Orofacial clefts (OFCs), including cleft lip with or without cleft palate (CL/P) and cleft palate only (CPO), are commonly occurring human birth defects that cause significant morbidity and require extensive medical intervention. Inheritance patterns are non-Mendelian and in most cases, affected patients have no positive family history [1,2,3]. This suggests that OFCs result from interacting genetic and environmental factors. The Hedgehog (Hh) signaling pathway is required for development of the brain and face. Sonic Hedgehog (Shh) is detected in the neuroectoderm of the ventral mesencephalon, with expression expanding rostrally into the diencephalon and telencephalon [5, 6]. Along with its well-described role in neurospecification, expression of Shh in the forebrain neuroectoderm is required for patterning and expansion of the adjacently developing midface [7, 8]. Pathway activity is detected in the medial nasal processes that contribute to the median aspect of the upper lip and primary palate, as well as the maxillary processes that give rise to the lateral aspects of the upper lip and the secondary palate [9, 10]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
