Premature suture closure and ectopic cranial bone in mice expressing Msx2 transgenes in the developing skull.

Abstract

The coordinate growth of the brain and skull is achieved through a series of interactions between the developing brain, the growing bones of the skull, and the fibrous joints, or sutures, that unite the bones. These interactions couple the expansion of the brain to the growth of the bony plates at the sutures. Craniosynostosis, the premature fusion of the bones of the skull, is a common birth defect (1 in 3000 live births) that disrupts coordinate growth and often results in profoundly abnormal skull shape. Individuals affected with Boston-type craniosynostosis, an autosomal dominant disorder, bear a mutated copy ofMSX2, a homeobox gene thought to function in tissue interactions. Here we show that expression of the mouse counterpart of this mutant gene in the developing skulls of transgenic mice causes craniosynostosis and ectopic cranial bone. These mice provide a transgenic model of craniosynostosis as well as a point of entry into the molecular mechanisms that coordinate the growth of the brain and skull.

Msx2 promotes cardiovascular calcification by activating paracrine Wnt signals

“…CMV-Msx2 and TOPGAL + ;CMV-Msx2Tg + mice (C57Bl/6 background) were generated essentially as described (26). A single line yielding Msx2 transgene expression was analyzed.…”

“…Since high-fat diets promote vascular calcification in male LDLR -/-mice (14,25) and BMP2-Msx2 signaling promotes osteogenic mineralization of cultured myofibroblasts (10), we proposed that Msx2 exerts procalcific actions during macrovascular calcification in vivo. To test this notion, we generated CMV-Msx2Tg + (cytomegalovirus immediate early promoter-Msx2 transgenic) mice, a model previously demonstrated to recapitulate features of Msx2 action during craniosynostosis (26). We examined effects in LDLR + C57Bl/6 mice, a background of intermediate susceptibility to diet-induced vascular disease as compared with LDLR -/-mice (27).…”

“…First, we used the CMV promoter to enhance aortic Msx2 expression in vivo. CMVMsx2Tg + mice have been previously validated for the study of gainof-function features of Msx2 relevant to ectopic calvarial suture mineralization (26) and represented a logical choice for our initial studies. Unlike the relatively nonselective transcriptional activity exhibited following transient transfection, the CMV immediate early promoter exhibits cell-type specificity in transgenic mice (28).…”

Postnatal Msx1 expression pattern in craniofacial, axial, and appendicular skeleton of transgenic mice from the first week until the second year

“…Several divergent homeogenes have been proposed as alternative candidates for the patterning of craniofacial skeleton. Among these genes, members of Msx (Muscle segment homeobox gene) have recently retained much attention regarding the distinct disruption of early skeletal development in their transgenic null mutant mice (Houzelstein et al, 1997;Liu et al, 1995;Satokata and Maas, 1994;Satokata et al, 2000), and site-specific disorders of the skeleton related to human gene mutations (Francomano et al, 1996;Hollway et al, 1995;Jabs et al, 1993;van den Boogaard et al, 2000;Vastardis et al, 1996) and polymorphism (Hwang et al, 1998). Bone formation occurs through two distinct differentiation pathways.…”

Erk1/2 signaling is required for Tgf‐β2–induced suture closure

“…Of these, mutations in the genes for several factors, their receptors, or downstream signaling molecules have been implicated in craniosynostosis, or the premature obliteration of sutures. The first identified mutations were in genes for transcription factors MSX2 and TWIST (Jabs et al, 1993(Jabs et al, , 1994Liu et al, 1994Liu et al, , 1995el Ghouzzi et al, 1997;Howard et al, 1997). Mutations in genes for fibroblast growth factor receptor (FGFR) and transforming growth factor ␤ (TGF-␤) receptor II (T␤R-II) have also been associated with craniosynostotic disorders (Muenke et al, 1994;Wilkie et al, 1995;Bellus et al, 1996;Loeys et al, 2005).…”