Inactivation of Six2 in mouse identifies a novel genetic mechanism controlling development and growth of the cranial base.
The cranial base is essential for integrated craniofacial development and growth. It develops as a cartilaginous template that is replaced by bone through the process of endochondral ossification. Here, we describe a novel and specific role for the homeoprotein Six2 in the growth and elongation of the cranial base. Six2-null newborn mice display premature fusion of the bones in the cranial base. Chondrocyte differentiation is abnormal in the Six2-null cranial base, with reduced proliferation and increased terminal differentiation. Gain-of-function experiments indicate that Six2 promotes cartilage development and growth in other body areas and appears therefore to control general regulators of chondrocyte differentiation. Our data indicate that the main factors restricting Six2 function to the cranial base are tissue-specific transcription of the gene and compensatory effects of other Six family members. The comparable expression during human embryogenesis and the high protein conservation from mouse to human implicate SIX2 loss-of-function as a potential congenital cause of anterior cranial base defects in humans.
School of Dentistry, Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9PT, UK.
Guiyuan
G
He
Sara
S
Tavella
Karen Piper
KP
Hanley
Michelle
M
Self
Guillermo
G
Oliver
Raphaëlle
R
Grifone
Neil
N
Hanley
Christopher
C
Ward
Nicoletta
N
Bobola
D000818:Animals; D000831:Animals, Newborn; D001842:Bone and Bones; D002356:Cartilage / Q000254:growth & development / Q000378:metabolism; D002454:Cell Differentiation; D020219:Chondrogenesis; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins; D010012:Osteogenesis / Q000502:physiology; D011506:Proteins / Q000378:metabolism; D019291:Skull Base / Q000254:growth & development*
D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D011506:Proteins; C484762:SIX2 protein, human