Elevated Id2 expression results in precocious neural stem cell depletion and abnormal brain development

Hee Jung Park, Mingi Hong, Roderick T Bronson, Mark A Israel, Wayne N Frankel, Kyuson Yun

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Id2 is a helix-loop-helix transcription factor essential for normal development, and its expression is dysregulated in many human neurological conditions. Although it is speculated that elevated Id2 levels contribute to the pathogenesis of these disorders, it is unknown whether dysregulated Id2 expression is sufficient to perturb normal brain development or function. Here, we show that mice with elevated Id2 expression during embryonic stages develop microcephaly, and that females in particular are prone to generalized tonic-clonic seizures. Analyses of Id2 transgenic brains indicate that Id2 activity is highly cell context specific: elevated Id2 expression in naive neural stem cells (NSCs) in early neuroepithelium induces apoptosis and loss of NSCs and intermediate progenitors. Activation of Id2 in maturing neuroepithelium results in less severe phenotypes and is accompanied by elevation of G1 cyclin expression and p53 target gene expression. In contrast, activation of Id2 in committed intermediate progenitors has no significant phenotype. Functional analysis with Id2-overexpressing and Id2-null NSCs shows that Id2 negatively regulates NSC self-renewal in vivo, in contrast to previous cell culture experiments. Deletion of p53 function from Id2-transgenic brains rescues apoptosis and results in increased incidence of brain tumors. Furthermore, Id2 overexpression normalizes the increased self-renewal of p53-null NSCs, suggesting that Id2 activates and modulates the p53 pathway in NSCs. Together, these data suggest that elevated Id2 expression in embryonic brains can cause deregulated NSC self-renewal, differentiation, and survival that manifest in multiple neurological outcomes in mature brains, including microcephaly, seizures, and brain tumors.

Original languageEnglish (US)
Pages (from-to)1010-21
Number of pages12
JournalStem cells (Dayton, Ohio)
Volume31
Issue number5
DOIs
StatePublished - May 2013

Keywords

  • Animals
  • Brain
  • Cell Differentiation
  • Cells, Cultured
  • Female
  • Inhibitor of Differentiation Protein 2
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neural Stem Cells
  • Journal Article
  • Research Support, N.I.H., Extramural

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