Foxc1 controls the growth of the murine frontal bone rudiment by direct regulation of a Bmp response threshold of Msx2.
The mammalian skull vault consists of several intricately patterned bones that grow in close coordination. The growth of these bones depends on the precise regulation of the migration and differentiation of osteogenic cells from undifferentiated precursor cells located above the eye. Here, we demonstrate a role for Foxc1 in modulating the influence of Bmp signaling on the expression of Msx2 and the specification of these cells. Inactivation of Foxc1 results in a dramatic reduction in skull vault growth and causes an expansion of Msx2 expression and Bmp signaling into the area occupied by undifferentiated precursor cells. Foxc1 interacts directly with a Bmp responsive element in an enhancer upstream of Msx2, and acts to reduce the occupancy of P-Smad1/5/8. We propose that Foxc1 sets a threshold for the Bmp-dependent activation of Msx2, thus controlling the differentiation of osteogenic precursor cells and the rate and pattern of calvarial bone development.
Department of Biochemistry and Molecular Biology, Norris Cancer Hospital, University of Southern California Keck School of Medicine, 1441 Eastlake Avenue, Los Angeles, CA 90089-9176, USA.
Jingjing
J
Sun
Mamoru
M
Ishii
Man-Chun
MC
Ting
Robert
R
Maxson
D000818:Animals; D001846:Bone Development / Q000235:genetics; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D019485:Bone Morphogenetic Proteins / Q000378:metabolism* / Q000494:pharmacology; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005624:Frontal Bone / Q000196:embryology* / Q000254:growth & development / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010012:Osteogenesis / Q000235:genetics / Q000502:physiology; D012886:Skull / Q000196:embryology / Q000378:metabolism
C525719:Bmp2 protein, mouse; C525810:Bmp4 protein, mouse; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D051858:Forkhead Transcription Factors; C112890:Foxc1 protein, mouse; D018398:Homeodomain Proteins; C084119:MSX2 protein