A study of the role of Msx genes in mammalian orgenogenesis

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To elucidate the role of the msh-class homebox genes Msx1 and Msx2 in mammalian organogenesis, we have analyzed knockout mice of these genes which are thought to be involved in epithelial-mesenchymal interaction during organogenesis. We had previously shown that Msx1 induced in the dental mesenchyme by BMP4 and FGF4 which are secreted from dental epithelium, in turn, induces BMP4, LEF1, and syndecan 1 in the dental mesenchyme and that Msx1 functions as a signal mediator between dental epithelium and mesenchyme. Msx2 mutants showed a failure of enamel formation. The reduced apoptosis in the first enamel knot of mutants seemed to be a cause of this developmental abnormality. The signaling pathway, i. e., BMP4→Msx2→BMP4→apoptosis exists and is considered to be essential for normal development of enamel organ. Msx2 mutants also manifested abnormal bone and cartliage formation. The number of osteoblasts and osteoclasts was deminished and the thickness of growth plate and cortical bone was t … More hin in the mutants. Expression of the differentiation markers for osteoblasts Cbfa1, osteonectin, Alp, osteopontin, BSP, and osteocalsin were decreased in the developing long bone of the mutants. Expression of the differentiation markers for chondrocytes ColII, ColX, PTHrP, and PTH/PTHrP receptor were also reduced in the mutants. Msx2 may play an important role for the transcriptional regulation of these genes. Msx1 ・ Msx2 double mutants manifested hypoplastic thumbs, polydactyly, syndactyly, and absence of radius and tibia. In E10.5 double mutants limb bud, the expression of Shh in the zone of polarizing activity (ZPA) could not be detecedby in situ hybridization anf Fgf4 expression was shifted from the posterior half of the apical ectdermal ridge (AER) to the anterior half. Msx1 and Msx2 function upstream of Shh, and are required for the expression of Shh in the limb ZPA. Bmp4 expression in the anterior portion of the progress zone also could not be detected in double mutants. The abnormal expression of these genes is thought to cause hypoplastic thumbs, polydactyly, and absence of radius and tibia. Furthermore, Bmp4 expression was markedly reduced and inhibition of apoptosis was observed in E10.5 interdigital region of double mutants. Inhibition of apoptosis in interdigital region can cause polydactyly. Msx1 and Msx2 are required for the Bmp4 expression in the anterior portion of progress zone and interdigital region, and the signal pathway, i. e. ., BMP and FGF from AER→Msx1 and Msx2→BMP4 in progress zone and interdigital region functions for normal limb formation. In summary, Msx1 and Msx2 are thought to function as important signal mediators in the epithelial-mesenchymal interaction during organogenesis. Less