Wnt/β-catenin signaling and Msx1 promote outgrowth of the maxillary prominences

Marie Medio,Erika Yeh,Jill A Helms,Antoine Popelut,Ariane Berdal,Sylvie Babajko

doi:10.3389/fphys.2012.00375

Marie Medio, Erika Yeh + Show 4 more

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https://doi.org/10.3389/fphys.2012.00375

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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 Msx1 is a key participant in these molecular events, as demonstrated by the palatal clefting phenotype observed in Msx1−/− 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 Msx1 function in CP. Histomorphometric analyses indicated that facial development was disrupted as early as E12.5 in Msx1−/− embryos, long before the palatal shelves have formed. By mapping the expression domain of Msx1 in E11.5 and E12.5 embryos, we found the structures most affected by loss of Msx1 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 Msx1 expression by the Wnt/β-catenin pathway is highly specific. Our data in mice and chicks indicate a conserved role for Msx1 in regulating the outgrowth of the maxillary prominences, and underscore how imbalances in Msx1 function can lead of growth disruptions that manifest as CP.

Highlights

Mid-facial morphogenesis involves the choreographed growth of the facial prominences with each other and with other regions of the growing head
At later stages of development, Msx1 is restricted to the anterior part of the palatal shelves (Zhang et al, 2002; Hilliard et al, 2005) and Msx1−/− embryos show complete secondary cleft palate (Satokata and Maas, 1994)
The cleft palate phenotype has been attributed to cell proliferation defects in the anterior region of the developing palatal shelves at E13.5 (Hu et al, 2001; Zhang et al, 2002; Levi et al, 2006) but our analyses demonstrate that loss of Msx1 disturbs facial developmental events as early as E12.5 (Figures 1, 2)

Summary

Introduction

Mid-facial morphogenesis involves the choreographed growth of the facial prominences with each other and with other regions of the growing head When this highly synchronized process is disrupted, by either genetic or environmental influences, the result is cleft lip, cleft palate (CP), and the combination [CL/P; (Dixon et al, 2011)]. During later stages of fetal development do species-specific facial characteristics emerge (Brugmann et al, 2006). This conservation in facial morphology is paralleled by an robust conservation in the gene regulatory networks that shape the face (Brugmann and Moody, 2005; Juriloff and Harris, 2008). Genetic models and experimental manipulations can provide useful insights into the molecular regulation of facial form

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