A Recessive ENU Screen Identifies Memo as a Novel Gene Driving Palatogenesis and Cranial base Development

Abstract

Nearly 75% of all birth defects affect the head and orofacial complex, with ~1:750 live births involving a facial cleft. To identify novel genes driving orofacial development we employed a recessive ENU screen and recovered a mutant line which developed a shortened cranial base as well as a fully penetrant cleft secondary palate. Mapping identified the causative gene to be Mediator of ErbB2 Driven Cell Motility (Memo). We confirmed the role of Memo in the embryonic phenotype using an available knockout (KO) allele coupled with non-complementation analysis. Further analysis of the facial phenotype identified a general failure in palatal shelf elevation as well as disruption of bones of the cranial base and anterior craniofacial skeleton. As these phenotypes are consistent with a neural crest (NC) defect, we used Wnt1-Cre to delete Memo in this tissue and confirmed a cell-autonomous role for Memo in these cells. Early specification and migration of NC is not grossly affected in mutants, placing Memo's role downstream of these developmental processes. Current analyses are aimed at determining if Memo mutation is affecting the function of “a receptor tyrosine kinase” or “of receptor tyrosine kinases” linked with facial development as well as associated cytoskeletal and cell migration processes, or whether the phenotype reflects the recently discovered role of Memo in regulating redox potential during migration. In summary, our findings demonstrate that Memo can function in the NC to drive palatogenesis and cranial base morphogenesis. Funding: EVO, American Association of Anatomists, NIH/NIDCR, Cleft Palate Foundation