Role of skeletal muscle in palate development.

The involvement of skeletal muscle in the process of palatal development in mammals is an example of Waddingtonian epigenetics. Our earlier study showed that the cleft palate develops in the complete absence of skeletal musculature during embryonic development in mice. This contrasts with previous beliefs that tongue obstruction prevents the elevation and fusion of the palatal shelves. We argue that the complete absence of mechanical stimuli from the adjacent muscle, i.e., the lack of both static and dynamic loading, results in disordered palatogenesis. We further suggest that proper fusion of the palatal shelves depends not only on mechanical but also on paracrine contributions from the muscle. The muscle's paracrine role in the process of palatal fusion is achieved through its being a source of certain secreted and/or circulatory proteins. A cDNA microarray analysis revealed differentially expressed genes in the cleft palate of amyogenic mouse fetuses and suggested candidate molecules with a novel function in palatogenesis (e.g., Tgfbr2, Bmp7, Trim71, E2f5, Ddx5, Gfap, Sema3f). In particular, we report on Gdf11 mutant mouse that has cleft palate, and on several genes whose distribution is normally restricted to the muscle (completely absent in our amyogenic mouse model), but which are found down-regulated in amyogenic mouse cleft palate. These molecules probably present a subset of paracrine cues that influence palatogenesis from the adjacent muscle. Future studies will elucidate the role of these genes in muscle-palate crosstalk, connecting the cues produced by the muscle with the cartilage and bone tissue's responses to these cues, through various degrees of cell proliferation, death, differentiation and tissue fusion.