Functions of Intracellular Regulators of Notch Signaling

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Mastermind (Mam) is one of the evolutionarily conserved elements of Notch signaling. Genetic analyses in Drosophila implicated it as an essential positive regulator of the pathway. We had identified mammalian Mam family of proteins that consists of three members (Mam-1,Mam-2 and Mam-3), and elucidated biochemical mechanism of action of the Mam proteins. All three human and Drosophila Mam stabilize and participate in the DNA binding complex of a CSL DNA-binding protein and the Notch intracellular domains that serve as intermediates of the signaling. All the Mam proteins enhanced the activation of transcription from target promoters by Notch signaling.In order to elucidate the in vivo function of the Mam in a mammalian system, we have generated mouse strains deficient in Mam-1 and Mam-2 by homologous recombination. Mam-1-deficient mice exhibit growth retardation. This phenotype is apparent at the perinatal stage and exacerbated in their postnatal period. The mice succumb before weaning, indicating that Mam-1 has a non-redundant function and is an essential gene. In contrast, we have not identified major developmental defect in Mam-2-deficient mice. Furthermore, no defect has been found in hematopoietic system including T and B lymphocytes of the Mam-2-deficient mice. These results indicate that the Mam loci have distinct function in the vertebrate system.Congenital disorder of glycosylation IIc (CDG IIc) is a recessive syndrome characterized by slowed growth, mental retardation, and severe immunodeficiency. Recently, the gene responsible for CDG IIc was found to encode a GDP-fucose transporter. GDP-fucose is known to be essential for the fucosylation of N-linked glycans and for O-fucosylation, and both fucose modifications are present on Notch. We found that mammalian Gfr is required for Notch signaling in mammalian cultured cells. Therefore, reduced Notch signaling is implicated in the pathology of CDG IIc.