MAB21L2, a vertebrate member of the male-abnormal 21 family, modulates BMP signaling and interacts with SMAD1

Background: Through in vivo loss-of-function studies, vertebrate members of the Male abnormal 21 ( mab-21) gene family have been implicated in gastrulation, neural tube formation and eye morphogenesis. Despite mounting evidence of their considerable importance in development, the biochemical properties and nature of MAB-21 proteins have remained strikingly elusive. In addition, genetic studies conducted in C. elegans have established that in double mutants mab-21 is epistatic to genes encoding various members of a Transforming Growth Factor beta ( TGF-beta) signaling pathway involved in the formation of male-specific sensory organs. Results: Through a gain-of-function approach, we analyze the interaction of Mab2112 with a TGFbeta signaling pathway in early vertebrate development. We show that the vertebrate mab-21 homolog Mab2112 antagonizes the effects of Bone Morphogenetic Protein 4 ( BMP4) overexpression in vivo, rescuing the dorsal axis and restoring wild-type distribution of Chordin and Xvent2 transcripts in Xenopus gastrulae. We show that MAB21L2 immunoprecipitates in vivo with the BMP4 effector SMAD1, whilst in vitro it binds SMAD1 and the SMAD1-SMAD4 complex. Finally, when targeted to an heterologous promoter, MAB21L2 acts as a transcriptional repressor. Conclusions: Our results provide the first biochemical and cellular foundation for future functional studies of mab-21 genes in normal neural development and its pathological disturbances.