title: The repression of Notch signaling occurs via the destabilization of mastermind-like 1 by Mesp2 and is essential for somitogenesis.
abstract: The rostro-caudal polarity within a somite is primarily determined by the on/off state of Notch signaling, but the mechanism by which Notch is repressed has remained elusive. Here, we present genetic and biochemical evidence that the suppression of Notch signaling is essential for the establishment of rostro-caudal polarity within a somite and that Mesp2 acts as a novel negative regulator of the Notch signaling pathway. We generated a knock-in mouse in which a dominant-negative form of Rbpj is introduced into the Mesp2 locus. Intriguingly, this resulted in an almost complete rescue of the segmental defects in the Mesp2-null mouse. Furthermore, we demonstrate that Mesp2 potently represses Notch signaling by inducing the destabilization of mastermind-like 1, a core regulator of this pathway. Surprisingly, this function of Mesp2 is found to be independent of its function as a transcription factor. Together, these data demonstrate that Mesp2 is a novel component involved in the suppression of Notch target genes.
authors.affiliation: Division of Mammalian Development, National Institute of Genetics, Yata 1111, Mishima, Shizuoka 411-8540, Japan.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Sasaki
authors.forename: Makoto
authors.initials: M
authors.lastname: Kiso
authors.forename: Motoo
authors.initials: M
authors.lastname: Kitagawa
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Saga
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002478:Cells, Cultured; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D019170:Somites / Q000196:embryology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D009687:Nuclear Proteins; D051880:Receptors, Notch; D014157:Transcription Factors; C486455:Maml1 protein, mouse; C107407:Mesp2 protein, mouse