Identifying genes important for spermatogonial stem cell self-renewal and survival

Jon M Oatley; Mary R Avarbock; Aino I Telaranta; Douglas T Fearon; Ralph L Brinster

doi:10.1073/pnas.0603332103

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Identifying genes important for spermatogonial stem cell self-renewal and survival

Journal article

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Identifying genes important for spermatogonial stem cell self-renewal and survival

Jon M Oatley, Mary R Avarbock, Aino I Telaranta, Douglas T Fearon and Ralph L Brinster

Proceedings of the National Academy of Sciences - PNAS, Vol.103(25), pp.9524-9529

06/20/2006

DOI: https://doi.org/10.1073/pnas.0603332103

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https://hdl.handle.net/2376/109530

PMCID: PMC1480440

PMID: 16740658

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Abstract

Spermatogonia - drug effects

Cell Proliferation

Oligonucleotide Array Sequence Analysis

Cell Survival

Mice, Inbred C57BL

Cells, Cultured

Gene Expression Regulation

Thymus Gland - cytology

Glial Cell Line-Derived Neurotrophic Factor Receptors - metabolism

Repressor Proteins - genetics

Male

Thymus Gland - drug effects

Down-Regulation - drug effects

Stem Cells - metabolism

Stem Cells - chemistry

Spermatogonia - metabolism

Glial Cell Line-Derived Neurotrophic Factor - metabolism

Animals

Time Factors

Glial Cell Line-Derived Neurotrophic Factor - pharmacology

Stem Cells - drug effects

Cell Differentiation

Mice

Spermatogonia - cytology

Spermatogonial stem cells (SSCs) are the foundation for spermatogenesis and, thus, preservation of a species. Because of stem cell rarity, studying their self-renewal is greatly facilitated by in vitro culture of enriched biologically active cell populations. A recently developed culture method identified glial cell line-derived neurotrophic factor (GDNF) as the essential growth factor that supports in vitro self-renewal of SSCs and results in an increase in their number. This system is a good model to study mechanisms of stem cell self-renewal because of the well defined culture conditions, enriched cell population, and available transplantation assay. By withdrawing and replacing GDNF in culture medium, we identified regulated expression of many genes by using microarray analysis. The expression levels of six of these genes were dramatically decreased by GDNF withdrawal and increased by GDNF replacement. To demonstrate the biological significance of the identified GDNF-regulated genes, we examined the importance of the most responsive of the six, bcl6b, a transcriptional repressor. By using siRNA to reduce transcript levels, Bcl6b was shown to be crucial for SSC maintenance in vitro. Moreover, evaluation of Bcl6b-null male testes revealed degeneration and/or absence of active spermatogenesis in 24 +/- 7% of seminiferous tubules. These data suggest that Bcl6b is an important molecule in SSC self-renewal and validate the biological relevance of the GDNF-regulated genes identified through microarray analysis. In addition, comparison of data generated in this study to other stem cell types suggests that self-renewal in SSCs is regulated by distinctly different molecular mechanisms.

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Title: Identifying genes important for spermatogonial stem cell self-renewal and survival
Creators: Jon M Oatley - Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, 3850 Baltimore Avenue, Philadelphia, PA 19104, USA
Mary R Avarbock
Aino I Telaranta
Douglas T Fearon
Ralph L Brinster
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.103(25), pp.9524-9529
Academic Unit: Molecular Biosciences, School of
Publisher: United States
Grant note: R01 AG024992 / NIA NIH HHS HD 044445 / NICHD NIH HHS AG 024992 / NIA NIH HHS 5P30 DK 47747-07 / NIDDK NIH HHS R01 HD044445 / NICHD NIH HHS
Identifiers: 99900547282201842
Language: English
Resource Type: Journal article