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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. S TEM  C ELLS  2013;31:1010–1021

Elevated Id2 Expression Results in Precocious Neural Stem Cell Depletion and Abnormal Brain Development