The N-Myc-DLL3 cascade is suppressed by the ubiquitin ligase Huwe1 to inhibit proliferation and promote neurogenesis in the developing brain

Dev Cell. 2009 Aug;17(2):210-21. doi: 10.1016/j.devcel.2009.07.009.

Abstract

Self-renewal and proliferation of neural stem cells and the decision to initiate neurogenesis are crucial events directing brain development. Here we show that the ubiquitin ligase Huwe1 operates upstream of the N-Myc-DLL3-Notch pathway to control neural stem cell activity and promote neurogenesis. Conditional inactivation of the Huwe1 gene in the mouse brain caused neonatal lethality associated with disorganization of the laminar patterning of the cortex. These defects stemmed from severe impairment of neurogenesis associated with uncontrolled expansion of the neural stem cell compartment. Loss- and gain-of-function experiments in the mouse cortex demonstrated that Huwe1 restrains proliferation and enables neuronal differentiation by suppressing the N-Myc-DLL3 cascade. Notably, human high-grade gliomas carry focal hemizygous deletions of the X-linked Huwe1 gene in association with amplification of the N-myc locus. Our results indicate that Huwe1 balances proliferation and neurogenesis in the developing brain and that this pathway is subverted in malignant brain tumors.

Publication types

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

MeSH terms

  • Animals
  • Brain* / cytology
  • Brain* / embryology
  • Cell Cycle / physiology
  • Cell Differentiation / physiology
  • Cell Proliferation
  • Cells, Cultured
  • Epigenesis, Genetic
  • Female
  • Gene Expression Profiling
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Neurogenesis / physiology*
  • Oligonucleotide Array Sequence Analysis
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / metabolism
  • Signal Transduction / physiology*
  • Stem Cells / cytology
  • Stem Cells / physiology*
  • Tumor Suppressor Proteins
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • Dll3 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Notch1 protein, mouse
  • Proto-Oncogene Proteins c-myc
  • Receptor, Notch1
  • Tumor Suppressor Proteins
  • Huwe1 protein, mouse
  • Ubiquitin-Protein Ligases