Wnt/β-catenin signaling and Ms×1 promote outgrowth of the maxillary prominences

Abstract

Facial morphogenesis requires a series of precisely orchestrated molecular events to promote the growth and fusion of the facial prominences. Cleft palate (CP) results from perturbations in this process. The transcriptional repressor Ms×1 is a key participant in these molecular events, as demonstrated by the palatal clefting phenotype observed in Ms×1 -/- embryos. Here, we exploited the high degree of conservation that exists in the gene regulatory networks that shape the faces of birds and mice, to gain a deeper understanding of Ms×1 function in CP. Histomorphometric analyses indicated that facial development was disrupted as early as E12.5 in Ms×1 -/- embryos, long before the palatal shelves have formed. By mapping the expression domain of Ms×1 in E11.5 and E12.5 embryos, we found the structures most affected by loss of Ms×1 function were the maxillary prominences. Maxillary growth retardation was accompanied by perturbations in angiogenesis that preceded the CP phenotype. Experimental chick manipulations and in vitro assays showed that the regulation of Ms×1 expression by the Wnt/β-catenin pathway is highly specific. Our data in mice and chicks indicate a conserved role for Ms×1 in regulating the outgrowth of the maxillary prominences, and underscore how imbalances in Ms×1 function can lead of growth disruptions that manifest as CP. © 2012 Medio, Yeh, Popelut, Babajko, Berdal and Helms.