Testicular Architecture Is Critical for Mediation of Retinoic Acid Responsiveness by Undifferentiated Spermatogonial Subtypes in the Mouse

• Published in: Stem cell reports Vol. 10; no. 2; pp. 538 - 552
• Main Authors: Lord, Tessa, Oatley, Melissa J., Oatley, Jon M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.02.2018; Elsevier
• Subjects: Adult Germline Stem Cells - cytology; Adult Germline Stem Cells - drug effects; Animals; Cell Differentiation - drug effects; Cell Differentiation - genetics; Cell Lineage - drug effects; GFRA1; ID4; Male; Mice; RAR gamma; retinoic acid; Seminiferous Tubules - cytology; Seminiferous Tubules - growth & development; Spermatogenesis - drug effects; Spermatogenesis - genetics; Spermatogonia - cytology; Spermatogonia - growth & development; spermatogonial stem cells; Testis - cytology; Testis - growth & development; Tretinoin - administration & dosage; Tretinoin - metabolism; ID4; RAR gamma; retinoic acid; GFRA1; spermatogonial stem cells
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2018.01.003

Spermatogenesis requires retinoic acid (RA) induction of the undifferentiated to differentiating transition in transit amplifying (TA) progenitor spermatogonia, whereas continuity of the spermatogenic lineage relies on the RA response being suppressed in spermatogonial stem cells (SSCs). Here, we discovered that, in mouse testes, both spermatogonial populations possess intrinsic RA-response machinery and exhibit hallmarks of the differentiating transition following direct exposure to RA, including loss of SSC regenerative capacity. We determined that SSCs are only resistant to RA-driven differentiation when situated in the normal topological organization of the testis. Furthermore, we show that the soma is instrumental in “priming” TA progenitors for RA-induced differentiation through elevated RA receptor expression. Collectively, these findings indicate that SSCs and TA progenitor spermatogonia inhabit disparate niche microenvironments within seminiferous tubules that are critical for mediating extrinsic cues that drive fate decisions. •Contrary to previous dogma, SSCs do express RARγ, as well as other RAR/RXR variants•Following direct exposure, SSCs exhibit an RA signaling response•SSCs are protected from RA by the niche microenvironment in the testis•Signals from the soma prime progenitors for RA-driven differentiation Lord et al. have demonstrated that, contrary to previous assumptions, spermatogonial stem cells do express a functional complement of retinoic acid and retinoid X receptors (RARs/RXRs) and rely on protection from an undisturbed niche microenvironment to prevent loss of the spermatogenic reservoir to RA-induced differentiation.