Document Detail


Conditional and domain-specific inactivation of the Tsc2 gene in neural progenitor cells.
MedLine Citation:
PMID:  23359422     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Tuberous sclerosis complex (TSC) is a genetic disease characterized by multiorgan benign tumors as well as neurological manifestations. Epilepsy and autism are two of the more prevalent neurological complications and are usually severe. TSC is caused by mutations in either the TSC1 (encodes hamartin) or the TSC2 (encodes tuberin) genes with TSC2 mutations being associated with worse outcomes. Tuberin contains a highly conserved GTPase-activating protein (GAP) domain that indirectly inhibits mammalian target of rapamycin complex 1 (mTORC1). mTORC1 dysregulation is currently thought to cause much of the pathogenesis in TSC but mTORC1-independent mechanisms may also contribute. We generated a novel conditional allele of Tsc2 by flanking exons 36 and 37 with loxP sites. Mice homozygous for this knock-in Tsc2 allele are viable and fertile with normal appearing growth and development. Exposure to Cre recombinase then creates an in-frame deletion involving critical residues of the GAP domain. Homozygous conditional mutant mice generated using Emx1(Cre) have increased cortical mTORC1 signaling, severe developmental brain anomalies, seizures, and die within 3 weeks. We found that the normal levels of the mutant Tsc2 mRNA, though GAP-deficient tuberin protein, appear unstable and rapidly degraded. This novel animal model will allow further study of tuberin function including the requirement of the GAP domain for protein stability.
Authors:
Cary Fu; Kevin C Ess
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-03-13
Journal Detail:
Title:  Genesis (New York, N.Y. : 2000)     Volume:  51     ISSN:  1526-968X     ISO Abbreviation:  Genesis     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-04-22     Completed Date:  2013-10-17     Revised Date:  2014-04-02    
Medline Journal Info:
Nlm Unique ID:  100931242     Medline TA:  Genesis     Country:  United States    
Other Details:
Languages:  eng     Pagination:  284-92     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 Wiley Periodicals, Inc.
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MeSH Terms
Descriptor/Qualifier:
Alleles
Animals
Brain / abnormalities
Exons
Founder Effect
Gene Deletion
Gene Knock-In Techniques*
Homozygote
Mice
Mice, Transgenic
Neural Stem Cells / metabolism*
Protein Structure, Tertiary / genetics
TOR Serine-Threonine Kinases / genetics,  metabolism
Tumor Suppressor Proteins / chemistry,  genetics*
Grant Support
ID/Acronym/Agency:
1R01 NS078289/NS/NINDS NIH HHS; R01 NS078289/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/Tumor Suppressor Proteins; 0/tuberous sclerosis complex 1 protein; EC 2.7.1.1/TOR Serine-Threonine Kinases; EC 2.7.1.1/mTOR protein, mouse
Comments/Corrections

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