Characterization of new genes for BMP signaling pathway.

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TAK1, a member of the MAP kinase kinase kinase family, and its activator, TAB1, participate in the bone morphogenetic protein (BMP) signaling pathway involved in mesoderm induction and patterning in early Xenopus embryos.However, the events leading from receptor activation to TAK1 activation remain to be identified.A yeast interaction screen was used to search for proteins that function in the pathway linking the receptors and TAB1-TAK1.The human X-chromosome-linked inhibitor of apoptosis protein (XIAP) was isolated as a TAB1-binding protein.XIAP associated not only with TAB1 but also with the BMP receptors in mammalian cells. Injection of XIAP mRNA into dorsal blastomeres enhanced the ventralization of Xenopus embryos in a TAB1-TAK1-dependent manner.Furthermore, a truncated form of XIAP lacking the TAB1-binding domain partially blocked the expression of ventral mesodermal marker genes induced by a constitutively-active BMP type I receptor.Taken together, we identified that XIAP participates in the BMP signaling pathway as a positive regulator linking the BMP receptors and TAB1-TAK1.Recently, we isolated a murine homeobox-containing gene, distal-less 5 (mDlx5), as a BMP-inducible gene in osteoblastic MC3T3-E1 cells.Stable transfectants of MC3T3-E1 that overexpress mDlx5 mRNA showed increase in various osteogenic markers ; a 4-fold increase in alkaline phosphatase activity, a 6-fold increase in osteocalcin production and appearance in mineralization of extracellular matrix.Furthermore, mDlx5 was induced orthotopically in mouse embryos treated with BMP-4 and in fractured bone of adult mice. Consistent with these observations, we also found that injection of mDlx5 mRNA in dorsal blastomeres enhanced the ventralization of Xenopus embryos.Our results indicated that mDlx5 is a target gene of the BMP signaling pathway and acts as an important regulator of both osteogenesis and dorso-ventral patterning of embryonic axis.