The role of Notch signalling during mouse pharyngeal arch development

Abstract

During multiple tissue development, Notch signaling pathway plays essential roles in regulating cell proliferation, differentiation and cell fate determination. The Notch receptor interacts with ligands such Jagged and Delta on the adjacent cells, and subsequently, are cleaved and translocated to the nucleus, where it interacts with its co-activator RBPJ to transcriptionally regulate Hes and Hey. In humans, it has been reported that NOTCH2 and JAG1 mutations lead to craniofacial malformations in Alagille syndrome. In mice, haploinsufficience of Notch1 leads to abnormal cleft palate. However, how Notch signalling factors lead to the craniofacial abnormalities is not clearly understood. To study the function of Notch signalling during craniofacial development, we investigated the expression patterns of Notch signalling factors during pharyngeal arch development from E8.5 to E9.5, and examined the phenotypes of the RBPJ knockout and Notch1 overexpression mice. We found that Notch1, Jag1, DLL1, Lfng, Hes1 and Hey1 were expressed in the different populations of pharyngeal ectoderm progenitors, indicating that the Notch signaling pathway may contribute to the cell type specification in the developing pharyngeal arch. Using the Pax2-Cre to conditionally knock-out RBPJ in the pharyngeal ectoderm, we found that the epibranchial placodal cells committed to neurogenesis prematurely. However, overexpression of Notch1 intracellular domain by Pax2-Cre maintains the progenitor status of the pharyngeal epithelium. In summary, our results suggest that Notch signalling is critical in controlling the cell type specification of pharyngeal ectoderm, which would lead to the abnormal pharyngeal arch development in Notch signalling mutants.