Glial cell line-derived neurotrophic factor regulation of genes essential for self-renewal of mouse spermatogonial stem cells is dependent on Src family kinase signaling

Jon M Oatley; Mary R Avarbock; Ralph L Brinster

doi:10.1074/jbc.M703474200

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Glial cell line-derived neurotrophic factor regulation of genes essential for self-renewal of mouse spermatogonial stem cells is dependent on Src family kinase signaling

Journal article

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Glial cell line-derived neurotrophic factor regulation of genes essential for self-renewal of mouse spermatogonial stem cells is dependent on Src family kinase signaling

Jon M Oatley, Mary R Avarbock and Ralph L Brinster

The Journal of biological chemistry, Vol.282(35), pp.25842-25851

08/31/2007

DOI: https://doi.org/10.1074/jbc.M703474200

Handle:

https://hdl.handle.net/2376/114628

PMID: 17597063

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Abstract

Apoptosis - drug effects

Male

Stem Cells - cytology

Stem Cells - metabolism

Repressor Proteins - antagonists & inhibitors

Spermatogonia - metabolism

Stem Cell Transplantation

Glial Cell Line-Derived Neurotrophic Factor - metabolism

Glial Cell Line-Derived Neurotrophic Factor - pharmacology

Up-Regulation - physiology

src-Family Kinases - metabolism

Spermatogonia - cytology

Cell Line

DNA-Binding Proteins - antagonists & inhibitors

Homeodomain Proteins - biosynthesis

RNA, Small Interfering - pharmacology

Transcription Factors - antagonists & inhibitors

Transcription Factors - biosynthesis

Enzyme Activation - drug effects

Proto-Oncogene Proteins c-akt - biosynthesis

Up-Regulation - drug effects

Animals

Repressor Proteins - biosynthesis

Signal Transduction - drug effects

Homeodomain Proteins - antagonists & inhibitors

LIM-Homeodomain Proteins

Signal Transduction - physiology

Cell Proliferation - drug effects

Mice

Apoptosis - physiology

DNA-Binding Proteins - biosynthesis

Enzyme Activation - physiology

Self-renewal and differentiation by spermatogonial stem cells (SSCs) is the foundation for continual spermatogenesis. SSC self-renewal is dependent on glial cell line-derived neurotrophic factor (GDNF); however, intracellular mechanisms stimulated by GDNF in SSCs are unknown. To investigate these mechanisms we utilized a culture system that maintains a mouse undifferentiated germ cell population enriched for self-renewing SSCs. In these cultures mRNA for the transcription factors Bcl6b, Erm, and Lhx1 are up-regulated by GDNF and decreased in its absence. The expression of all three molecules was further identified in undifferentiated spermatogonia in vivo. Using small interfering RNA to reduce expression and transplantation to quantify stem cell numbers, Bcl6b, Erm, and Lhx1 were shown to be important for SSC maintenance in vitro. Next, GDNF was shown to activate both Akt and Src family kinase (SFK) signaling in SSCs, and culture of SSCs with inhibitors to Akt or SFKs followed by transplantation analysis showed significant impairment of SSC maintenance in vitro. Apoptosis analysis revealed a significant increase in the percentage of apoptotic cells when Akt, but not SFK, signaling was impaired, indicating that multiple signaling pathways are responsible for SSC self-renewal and survival. Biochemical and gene expression experiments revealed that GDNF up-regulated expression of Bcl6b, Erm, and Lhx1 transcripts is dependent on SFK signaling. Overall, these data demonstrate that GDNF up-regulation of Bcl6b, Erm, and Lhx1 expression through SFK signaling is a key component of the intracellular mechanism for SSC self-renewal.

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Title: Glial cell line-derived neurotrophic factor regulation of genes essential for self-renewal of mouse spermatogonial stem cells is dependent on Src family kinase signaling
Creators: Jon M Oatley - Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
Mary R Avarbock
Ralph L Brinster
Publication Details: The Journal of biological chemistry, Vol.282(35), pp.25842-25851
Academic Unit: Molecular Biosciences, School of
Publisher: United States
Grant note: HD052728 / NICHD NIH HHS R01 HD044445 / NICHD NIH HHS R01 HD052728 / NICHD NIH HHS HD044445 / NICHD NIH HHS
Identifiers: 99900548124401842
Language: English
Resource Type: Journal article