Document Detail


Spatial and temporal requirements for huntingtin (Htt) in neuronal migration and survival during brain development.
MedLine Citation:
PMID:  21994396     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Huntington's disease (HD), caused by an expanded triplet repeat in the huntingtin (Htt) gene, results in extensive neuropathology, but study of the Htt gene in CNS development through gene knockout is problematic as the knockout leads to embryonic lethality in mice. Here, we report that the knockdown of Htt expression in neuroepithelial cells of neocortex results in disturbed cell migration, reduced proliferation, and increased cell death that is relatively specific to early neural development. In the cerebellum, however, Htt knockdown results in cell death but not perturbed migration. The cell death phenotype in cortex can be partially reversed with co-knockdown of Casp9, indicating that mitochondria-mediated cell apoptotic processes are involved in the neuronal death. The timing of knockdown during early development is also an important variable. These results indicate a spatial and temporal requirement for Htt expression in neural development. Although it is uncertain whether the loss of wild-type huntingtin function contributes to pathogenesis in Huntington's disease, these results clearly contraindicate the use of nonspecific knockdown of Htt as a therapeutic measure in HD, particularly in utero.
Authors:
Yiai Tong; Thomas J Ha; Li Liu; Andrew Nishimoto; Anton Reiner; Dan Goldowitz
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of neuroscience : the official journal of the Society for Neuroscience     Volume:  31     ISSN:  1529-2401     ISO Abbreviation:  J. Neurosci.     Publication Date:  2011 Oct 
Date Detail:
Created Date:  2011-10-13     Completed Date:  2011-12-06     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  8102140     Medline TA:  J Neurosci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  14794-9     Citation Subset:  IM    
Affiliation:
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Brain* / cytology,  embryology,  metabolism
Bromodeoxyuridine / metabolism
Caspase 3 / metabolism
Caspase 9 / genetics,  metabolism
Cell Movement / genetics*
Cell Survival
Embryo, Mammalian
Female
Gene Expression Regulation, Developmental / genetics,  physiology*
Green Fluorescent Proteins / genetics
Male
Mice
Mice, Inbred ICR
Mice, Transgenic
Nerve Tissue Proteins / genetics,  metabolism*
Neurons / physiology*
Nuclear Proteins / genetics,  metabolism*
Pregnancy
RNA, Small Interfering / genetics
Time Factors
Grant Support
ID/Acronym/Agency:
HD 52472/HD/NICHD NIH HHS; R01 HD052472/HD/NICHD NIH HHS
Chemical
Reg. No./Substance:
0/Huntington protein, mouse; 0/Nerve Tissue Proteins; 0/Nuclear Proteins; 0/RNA, Small Interfering; 0/enhanced green fluorescent protein; 147336-22-9/Green Fluorescent Proteins; 59-14-3/Bromodeoxyuridine; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspase 9
Comments/Corrections

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