Msx2 deficiency in mice causes pleiotropic defects in bone growth and ectodermal organ formation

The composite structure of the mammalian skull, which forms predominantly v ia intramembranous ossification, requires precise pre- and post-natal growt h regulation of individual calvarial elements. Disturbances of this process frequently cause severe clinical manifestations in humans. Enhanced DNA bi nding by a mutant MSX2 homeodomain results in a gain of function and produc es craniosynostosis in humans(1,2). Here we show that Msx2-deficient mice h ave defects of skull ossification and persistent calvarial foramen, This ph enotype results from defective proliferation of osteoprogenitors at the ost eogenic front during calvarial morphogenesis, and closely resembles that as sociated with human MSX2 haploinsufficiency in parietal foramina(3) (PFM), Msx2(-/-) mice also have defects in endochondral bone formation. In the axi al and appendicular skeleton, post-natal deficits in Pth/Pthrp receptor (Pt hr) signalling and in expression of marker genes for bone differentiation i ndicate that Msx2 is required for both chondrogenesis and osteogenesis, Con sistent with phenotypes associated with PFM, Msx2-mutant mice also display defective tooth, hair follicle and mammary gland development, and seizures, the latter accompanied by abnormal development of the cerebellum. Most Msx 2-mutant phenotypes, including calvarial defects, are enhanced by genetic c ombination with Msx1 loss of function, indicating that Msx gene dosage can modify expression of the PFM phenotype. Our results provide a developmental basis for PFM and demonstrate that Msx2 is essential at multiple sites dur ing organogenesis.