Stem Cell Reports
Volume 9, Issue 3, 12 September 2017, Pages 956-971
Journal home page for Stem Cell Reports

Article
Germline Stem Cell Activity Is Sustained by SALL4-Dependent Silencing of Distinct Tumor Suppressor Genes

https://doi.org/10.1016/j.stemcr.2017.08.001Get rights and content
Under a Creative Commons license
open access

Highlights

  • Undifferentiated but not differentiating spermatogonia tolerate loss of SALL4

  • Long-term function of Sall4-deleted undifferentiated cells is compromised

  • SALL4 directly represses the tumor suppressor genes Foxl1 and Dusp4

  • FOXL1 and DUSP4 disrupt spermatogonial proliferation and self-renewal pathways

Summary

Sustained spermatogenesis in adult males and fertility recovery following germ cell depletion are dependent on undifferentiated spermatogonia. We previously demonstrated a key role for the transcription factor SALL4 in spermatogonial differentiation. However, whether SALL4 has broader roles within spermatogonia remains unclear despite its ability to co-regulate genes with PLZF, a transcription factor required for undifferentiated cell maintenance. Through development of inducible knockout models, we show that short-term integrity of differentiating but not undifferentiated populations requires SALL4. However, SALL4 loss was associated with long-term functional decline of undifferentiated spermatogonia and disrupted stem cell-driven regeneration. Mechanistically, SALL4 associated with the NuRD co-repressor and repressed expression of the tumor suppressor genes Foxl1 and Dusp4. Aberrant Foxl1 activation inhibited undifferentiated cell growth and survival, while DUSP4 suppressed self-renewal pathways. We therefore uncover an essential role for SALL4 in maintenance of undifferentiated spermatogonial activity and identify regulatory pathways critical for germline stem cell function.

Keywords

germline stem cells
self-renewal
transcription factors
tumor suppressor genes
spermatogonia
SALL4

Cited by (0)