Document Detail


Elevated Id2 expression results in precocious neural stem cell depletion and abnormal brain development.
MedLine Citation:
PMID:  23390122     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Hee Jung Park; Mingi Hong; Roderick T Bronson; Mark A Israel; Wayne N Frankel; Kyuson Yun
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Stem cells (Dayton, Ohio)     Volume:  31     ISSN:  1549-4918     ISO Abbreviation:  Stem Cells     Publication Date:  2013 May 
Date Detail:
Created Date:  2013-04-25     Completed Date:  2014-05-02     Revised Date:  2014-05-07    
Medline Journal Info:
Nlm Unique ID:  9304532     Medline TA:  Stem Cells     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1010-21     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 AlphaMed Press.
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MeSH Terms
Descriptor/Qualifier:
Animals
Brain / abnormalities*,  cytology*,  metabolism
Cell Differentiation / physiology
Cells, Cultured
Female
Inhibitor of Differentiation Protein 2 / biosynthesis*,  genetics,  metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Neural Stem Cells / cytology,  metabolism*
Grant Support
ID/Acronym/Agency:
CA034196/CA/NCI NIH HHS; NS031348/NS/NINDS NIH HHS; P30 CA034196/CA/NCI NIH HHS; R01 NS031348/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/Idb2 protein, mouse; 0/Inhibitor of Differentiation Protein 2
Comments/Corrections

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