Lack of the mesodermal homeodomain protein MEOX1 disrupts sclerotome polarity and leads to a remodeling of the cranio-cervical joints of the axial skeleton.
Meox1 and Meox2 are two related homeodomain transcription factor genes that together are essential for the development of all somite compartments. Here we show that mice homozygous for Meox1 mutations alone have abnormalities that are restricted to the sclerotome and its derivatives. A prominent and consistent phenotype of these mutations is a remodeling of the cranio-cervical joints whose major feature is the assimilation of the atlas into the basioccipital bone so that the skull rests on the axis. These abnormalities can be traced back to changes in the relative rates of cell proliferation in the rostral and caudal sclerotome compartments, and they are associated with alterations in the expression of at least three transcription factor genes, Tbx18, Uncx, and Bapx1. As previously observed for Bapx1, MEOX1 protein occupies evolutionarily conserved promoter regions of Tbx18 and Uncx, suggesting that Meox1 regulates these genes at least in part directly. Hence, Meox1 is part of a regulatory circuit that serves an essential, non-redundant function in the maintenance of rostro-caudal sclerotome polarity and axial skeleton formation.
Skuntz
Susan
S
Mammalian Development Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-3706, USA.
Mankoo
Baljinder
B
Nguyen
Minh-Thanh T
MT
Hustert
Elisabeth
E
Nakayama
Atsuo
A
Tournier-Lasserve
Elisabeth
E
Wright
Christopher V E
CV
Pachnis
Vassilis
V
Bharti
Kapil
K
Arnheiter
Heinz
H
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D019521:Body Patterning / Q000502:physiology*; D002574:Cervical Vertebrae / Q000002:abnormalities / Q000196:embryology*; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D017403:In Situ Hybridization; D007596:Joints / Q000002:abnormalities / Q000196:embryology*; D008648:Mesoderm / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D011401:Promoter Regions, Genetic; D012886:Skull / Q000002:abnormalities / Q000196:embryology*; D019170:Somites / Q000166:cytology / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D015415:Biomarkers; D018398:Homeodomain Proteins; C484871:Meox1 protein, mouse; C107965:Nkx3-2 protein, mouse; D020825:T-Box Domain Proteins; C420983:Tbx18 protein, mouse; D014157:Transcription Factors