title: Inactivation of Msx1 and Msx2 in neural crest reveals an unexpected role in suppressing heterotopic bone formation in the head.
abstract: In an effort to understand the morphogenetic forces that shape the bones of the skull, we inactivated Msx1 and Msx2 conditionally in neural crest. We show that Wnt1-Cre inactivation of up to three Msx1/2 alleles results in a progressively larger defect in the neural crest-derived frontal bone. Unexpectedly, in embryos lacking all four Msx1/2 alleles, the large defect is filled in with mispatterned bone consisting of ectopic islands of bone between the reduced frontal bones, just anterior to the parietal bones. The bone is derived from neural crest, not mesoderm, and, from DiI cell marking experiments, originates in a normally non-osteogenic layer of cells through which the rudiment elongates apically. Associated with the heterotopic osteogenesis is an upregulation of Bmp signaling in this cell layer. Prevention of this upregulation by implantation of noggin-soaked beads in head explants also prevented heterotopic bone formation. These results suggest that Msx genes have a dual role in calvarial development: They are required for the differentiation and proliferation of osteogenic cells within rudiments, and they are also required to suppress an osteogenic program in a cell layer within which the rudiments grow. We suggest that the inactivation of this repressive activity may be one cause of Wormian bones, ectopic bones that are a feature of a variety of pathological conditions in which calvarial bone development is compromised.
authors.affiliation: 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.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Roybal
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Wu
authors.forename: Jingjing
authors.initials: J
authors.lastname: Sun
authors.forename: Man-chun
authors.initials: MC
authors.lastname: Ting
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Schafer
authors.forename: Robert E
authors.initials: RE
authors.lastname: Maxson
mesh_terms: D000818:Animals; D019521:Body Patterning; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D051957:MSX1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009432:Neural Crest / Q000166:cytology* / Q000196:embryology / Q000378:metabolism; D010012:Osteogenesis / Q000235:genetics*; D012886:Skull / Q000196:embryology*
chemical_list: D019485:Bone Morphogenetic Proteins; D018398:Homeodomain Proteins; D051957:MSX1 Transcription Factor; C084119:MSX2 protein; C484084:Msx1 protein, mouse
references.citation: Am J Med Genet A. 2007 Dec 15;143A(24):3243-51
references.pmid: 18000970
references.citation: Kokubyo Gakkai Zasshi. 2005 Mar;72(1):19-27
references.pmid: 15856768
references.citation: Development. 2004 Oct;131(20):5153-65
references.pmid: 15459107
references.citation: Nat Genet. 1997 Jan;15(1):42-6
references.pmid: 8988167
references.citation: J Bone Miner Res. 1995 Dec;10(12):1978-87
references.pmid: 8619379
references.citation: J Anat. 2005 Nov;207(5):637-53
references.pmid: 16313397
references.citation: Nat Genet. 1999 Jan;21(1):70-1
references.pmid: 9916792
references.citation: Development. 1999 Apr;126(8):1571-80
references.pmid: 10079220
references.citation: Ann Anat. 2002 Jan;184(1):1-7
references.pmid: 11876477
references.citation: Hum Mol Genet. 2006 Apr 15;15(8):1319-28
references.pmid: 16540516
references.citation: Development. 1998 Apr;125(7):1241-51
references.pmid: 9477322
references.citation: J Histochem Cytochem. 1992 Oct;40(10):1457-63
references.pmid: 1527370
references.citation: Histochem Cell Biol. 1999 Jun;111(6):435-43
references.pmid: 10429965
references.citation: Front Oral Biol. 2008;12:197-208
references.pmid: 18391502
references.citation: Dev Biol. 2007 Nov 15;311(2):335-46
references.pmid: 17931618
references.citation: Development. 1992 Oct;116(2):297-307
references.pmid: 1283734
references.citation: J Bone Miner Res. 2008 Mar;23(3):305-13
references.pmid: 17967130
references.citation: Curr Biol. 1998 Dec 3;8(24):1323-6
references.pmid: 9843687
references.citation: Development. 2003 Dec;130(24):6131-42
references.pmid: 14597577
references.citation: Development. 2000 Apr;127(8):1607-16
references.pmid: 10725237
references.citation: Mech Dev. 2007 Sep-Oct;124(9-10):729-45
references.pmid: 17693062
references.citation: Development. 2009 Mar;136(5):855-64
references.pmid: 19201948
references.citation: Mech Dev. 2008 Sep-Oct;125(9-10):797-808
references.pmid: 18617001
references.citation: Dev Dyn. 2006 Sep;235(9):2353-75
references.pmid: 16680722
references.citation: J Exp Zool. 1986 Aug;239(2):289-93
references.pmid: 3746236
references.citation: Genesis. 2007 Aug;45(8):477-81
references.pmid: 17654563
references.citation: Dev Biol. 2002 Jan 1;241(1):106-16
references.pmid: 11784098