The function of Msx genes in regulating cranial neural crest cells

The homeobox genes Msx1 and Msx2 function as transcriptional regulators that control cellular proliferation and differentiation during normal embryonic development. Mutations in the Msx1 and Msx2 genes in mice disrupt tissue-tissue interactions and cause multiple craniofacial malformations. Although Msx1 and Msx2 are both expressed throughout the entire development period of the frontal bone, the frontal bone defect in Msx1 or Msx2 null mutants is rather mild, suggesting the possibility of functional compensation between Msx1 and Msx2 . To investigate this hypothesis, we generated Msx1-/-;Msx2 -/- mice. These double mutant embryos died at E17 to E18 and showed a severe frontal bone defect. The murine frontal bone derives entirely from cranial neural crest (CNC) cells. Interestingly, there was no apparent defect in CNC migration into the frontal bone primordium, indicating that Msx1 and Msx2 genes are specifically required during frontal bone development. Mechanistically, we provide the first in vivo evidence that Msx genes act upstream of Runx2 to mediate the fate determination of CNC cells during osteogenesis. In addition, we show that Msx1 and Msx2 are required for CNC cell proliferation and survival during frontal bone development. A change in the total Msx gene dosage affects CNC cell proliferation and survival, indicating that precisely regulated Msx gene expression is critical for normal craniofacial development.; Neural crest cells are multipotential progenitors that contribute to various cell and tissue types during embryogenesis. We have investigated the molecular and cellular mechanism by which the fate of neural crest cell is regulated during tooth development. Using a two-component genetic system for indelibly marking the progeny of neural crest cells, we provide in vivo evidence of a deficiency of CNC-derived dental mesenchyme in Msx1 null mutant mouse embryos. The deficiency of the CNC results from an elevated CDK inhibitor p19INK4d activity and the disruption of cell proliferation. Interestingly, in the absence of Msx1, the CNC-derived dental mesenchyme misdifferentiates and possesses properties consistent with a neuronal fate, possibly through a default mechanism. Attenuation of p19INK4d in Msx1 null mutant mandibular explants restores mitotic activity in the dental mesenchyme, demonstrating the functional significance of Msx1-mediated p19 INK4d expression in regulating CNC cell proliferation during odontogenesis. Collectively, our results demonstrate that homeobox gene Msx1 regulates the fate of CNC cells by controlling the progression of the cell cycle. Genetic mutation of Msx1 may alternatively instruct the fate of these progenitor cells during craniofacial development.