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Abstract
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.
Highlights
Entiation, are often referred to as fate decisions and are the basis for how adult stem cells are defined
We have recently identified glial cell line-derived neurotrophic factor (GDNF)-regulated genes in cultured self-renewing germ cell populations proven to be enriched for spermatogonial stem cells (SSCs) by functional transplantation [9] which provided a data base of candidate molecules that may be essential for regulating SSC fate decisions
The stem cell potential and enrichment of these cultures was confirmed by functional transplantation in which the cells generated colonies of donor-derived spermatogenesis in recipient testes (Fig. 1B)
Summary
Entiation, are often referred to as fate decisions and are the basis for how adult stem cells are defined. Very little is known about mechanisms regulating these SSC fate decisions, yet deciphering them is important for understanding male fertility and general adult stem cell biology. SSCs are capable of reestablishing spermatogenesis when transferred into a recipient testis; the functional transplantation system is the only current means to distinguish SSCs from Apr and Aal spermatogonia. GDNF-regulated Stem Cell Renewal Depends on SFK Signaling [5] In this system SSC self-renewal is critically dependent on glial cell line-derived neurotrophic factor (GDNF), a transforming growth factor  family member originally shown to be important for kidney morphogenesis and neuronal progenitor development [6]. GDNF has been shown to influence undifferentiated spermatogonia function in vivo [7] Based on both in vivo and in vitro studies, it has become widely accepted that GDNF is the critical growth factor for mouse SSC selfrenewal. GDNF is critical for rat SSC self-renewal in vitro [8], suggesting that the importance of this growth factor for SSC function may be conserved across mammalian species
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