Mind bomb 1 is essential for generating functional Notch ligands to activate Notch.
The Delta-Notch signaling pathway is an evolutionarily conserved intercellular signaling mechanism essential for cell fate specification. Mind bomb 1 (Mib1) has been identified as a ubiquitin ligase that promotes the endocytosis of Delta. We now report that mice lacking Mib1 die prior to embryonic day 11.5, with pan-Notch defects in somitogenesis, neurogenesis, vasculogenesis and cardiogenesis. The Mib1-/- embryos exhibit reduced expression of Notch target genes Hes5, Hey1, Hey2 and Heyl, with the loss of N1icd generation. Interestingly, in the Mib1-/- mutants, Dll1 accumulated in the plasma membrane, while it was localized in the cytoplasm near the nucleus in the wild types, indicating that Mib1 is essential for the endocytosis of Notch ligand. In accordance with the pan-Notch defects in Mib1-/- embryos, Mib1 interacts with and regulates all of the Notch ligands, jagged 1 and jagged 2, as well as Dll1, Dll3 and Dll4. Our results show that Mib1 is an essential regulator, but not a potentiator, for generating functional Notch ligands to activate Notch signaling.
Koo
Bon-Kyoung
BK
Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang, Kyungbuk, 790-784, South Korea.
Lim
Hyoung-Soo
HS
Song
Ran
R
Yoon
Mi-Jeong
MJ
Yoon
Ki-Jun
KJ
Moon
Jin-Sook
JS
Kim
Young-Woong
YW
Kwon
Min-Chul
MC
Yoo
Kyeong-Won
KW
Kong
Myung-Phil
MP
Lee
Jinie
J
Chitnis
Ajay B
AB
Kim
Cheol-Hee
CH
Kong
Young-Yun
YY
D000818:Animals; D001808:Blood Vessels / Q000196:embryology; D047108:Embryonic Development / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000196:embryology; D008024:Ligands; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011956:Receptors, Cell Surface / Q000378:metabolism; D051880:Receptors, Notch; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics*
D008024:Ligands; D008565:Membrane Proteins; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; C470629:MIB1 protein, mouse; D044767:Ubiquitin-Protein Ligases