Mind bomb1 is a ubiquitin ligase essential for mouse embryonic development and Notch signaling

Mech Dev. 2005 Oct;122(10):1106-17. doi: 10.1016/j.mod.2005.06.005.

Abstract

The Notch-Delta signaling pathway controls many conserved cell determination events. While the Notch end is fairly well characterized, the Delta end remains poorly understood. Mind bomb1 (MIB1) is one of two E3 ligases known to ubiquitinate Delta. We report here that a targeted mutation of Mib1 in mice results in embryonic lethality by E10.5. Mutants exhibit multiple defects due to their inability to modulate Notch signaling. As histopathology revealed a strong neurogenic phenotype, this study concentrates on characterizing the Mib1 mutant by analyzing Notch pathway components in embryonic neuroepithelium prior to developmental arrest. Premature neurons were observed to undergo apoptosis soon after differentiation. Aberrant neurogenesis is a direct consequence of lowered Hes1 and Hes5 expression resulting from the inability to generate Notch1 intracellular domain (NICD1). We conclude that MIB1 activity is required for S3 cleavage of the Notch1 receptor. These results have direct implications for manipulating the differentiation of neuronal stem cells and provide a putative target for the modulation of specific tumors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cell Differentiation / genetics
  • Embryo, Mammalian / chemistry
  • Embryonic Development* / genetics
  • Genes, Lethal*
  • Homeodomain Proteins / metabolism
  • Mice
  • Molecular Sequence Data
  • Mutation
  • Neurons / cytology
  • Protein Structure, Tertiary
  • RNA / analysis
  • RNA / metabolism
  • Repressor Proteins / metabolism
  • Signal Transduction
  • Transcription Factor HES-1
  • Ubiquitin-Protein Ligases / deficiency
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / physiology*

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Hes1 protein, mouse
  • Hes5 protein, mouse
  • Homeodomain Proteins
  • Repressor Proteins
  • Transcription Factor HES-1
  • RNA
  • MIB1 protein, mouse
  • Ubiquitin-Protein Ligases