Document Detail


Germ cell pluripotency, premature differentiation and susceptibility to testicular teratomas in mice.
MedLine Citation:
PMID:  22438569     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Testicular teratomas result from anomalies in germ cell development during embryogenesis. In the 129 family of inbred strains of mice, teratomas initiate around embryonic day (E) 13.5 during the same developmental period in which female germ cells initiate meiosis and male germ cells enter mitotic arrest. Here, we report that three germ cell developmental abnormalities, namely continued proliferation, retention of pluripotency, and premature induction of differentiation, associate with teratoma susceptibility. Using mouse strains with low versus high teratoma incidence (129 versus 129-Chr19(MOLF/Ei)), and resistant to teratoma formation (FVB), we found that germ cell proliferation and expression of the pluripotency factor Nanog at a specific time point, E15.5, were directly related with increased tumor risk. Additionally, we discovered that genes expressed in pre-meiotic embryonic female and adult male germ cells, including cyclin D1 (Ccnd1) and stimulated by retinoic acid 8 (Stra8), were prematurely expressed in teratoma-susceptible germ cells and, in rare instances, induced entry into meiosis. As with Nanog, expression of differentiation-associated factors at a specific time point, E15.5, increased with tumor risk. Furthermore, Nanog and Ccnd1, genes with known roles in testicular cancer risk and tumorigenesis, respectively, were co-expressed in teratoma-susceptible germ cells and tumor stem cells, suggesting that retention of pluripotency and premature germ cell differentiation both contribute to tumorigenesis. Importantly, Stra8-deficient mice had an 88% decrease in teratoma incidence, providing direct evidence that premature initiation of the meiotic program contributes to tumorigenesis. These results show that deregulation of the mitotic-meiotic switch in XY germ cells contributes to teratoma initiation.
Authors:
Jason D Heaney; Ericka L Anderson; Megan V Michelson; Jennifer L Zechel; Patricia A Conrad; David C Page; Joseph H Nadeau
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-03-21
Journal Detail:
Title:  Development (Cambridge, England)     Volume:  139     ISSN:  1477-9129     ISO Abbreviation:  Development     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-04-11     Completed Date:  2012-05-31     Revised Date:  2014-06-24    
Medline Journal Info:
Nlm Unique ID:  8701744     Medline TA:  Development     Country:  England    
Other Details:
Languages:  eng     Pagination:  1577-86     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adaptor Proteins, Signal Transducing
Age Factors
Animals
Cell Differentiation / genetics,  physiology*
Cell Proliferation
Cyclin D1 / metabolism
Cytogenetic Analysis
Female
Flow Cytometry
Genetic Predisposition to Disease / genetics*
Germ Cells / cytology*
Histological Techniques
Homeodomain Proteins / metabolism
Immunohistochemistry
Male
Mice
Mice, Inbred Strains
Pluripotent Stem Cells / cytology*
Proteins / metabolism
Real-Time Polymerase Chain Reaction
Species Specificity
Teratoma / genetics*
Testicular Neoplasms / genetics*
Grant Support
ID/Acronym/Agency:
CA7505/CA/NCI NIH HHS; HD059945/HD/NICHD NIH HHS; R00 HD059945/HD/NICHD NIH HHS; RR017980/RR/NCRR NIH HHS; RR031842/RR/NCRR NIH HHS; S10 RR017980/RR/NCRR NIH HHS; S10 RR031845/RR/NCRR NIH HHS; //Howard Hughes Medical Institute
Chemical
Reg. No./Substance:
0/Adaptor Proteins, Signal Transducing; 0/Ccnd1 protein, mouse; 0/Homeodomain Proteins; 0/Nanog protein, mouse; 0/Proteins; 0/Stra8 protein, mouse; 136601-57-5/Cyclin D1
Comments/Corrections

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