The temporal and tissue specific requirement of Msx genes in murine skull vault osteogenesis.

摘要

The homeobox genes Msx1 and Msx2 are set of transcription factors known to have both widespread and overlapping expression patterns throughout the developing murine embryo. Conventional inactivation of either or both of these genes has been associated with a variety of congenital abnormalities including defects in calvarial osteogenesis, palate formation, cardiac development, and embryonic lethality. Here we utilize conditional and temporal gene inactivation to investigate the role of these genes in the development of the murine skull vault.;Temporal inactivation of Msx2 revealed a window of requirement for cranial osteogenesis. Concerted loss of both Msx1 and Msx2 showed an unexpected ability of neural crest derived tissues to contribute to the formation of ectopic bone. Along with this we demonstrated a more extended requirement for the basic helix-loop-helix transcription factor, Twist1, which when mutated causes multiple cranial malformations including craniosynostosis. Although conditional inactivation of Msx1 and Msx2 in neural crest or mesoderm derived tissue did manifest deficient frontal and parietal bone development respectively, only mesodermal inactivation resulted in premature coronal suture fusion.;However, conditional targeting of Msx1 and Msx2 using either neural crest or mesoderm driven cre recombinase illustrated phenotypes in adjacent calvarial tissues. Consistent with the view that Msx1 and Msx2 are required for specific tissue-tissue interactions in vertebrate development, here I show that these genes act upstream of BMP4 in cranial mesoderm to initiate and maintain osteogenesis in both the parietal and posterior frontal bone regions.;Together my data suggest (1) that Msx1, Msx2, and Twist1 have a crucial window of requirement in the formation of the murine skull vault, (2) that mesoderm derived Msx1 and Msx2 function upstream of the morphogen BMP4 to influence posterior frontal bone osteogenesis, (3) that mesoderm derived Msx1 and Msx2 establish and maintain non-osteogenic coronal suture mesenchyme.