ATRA and KL promote differentiation toward the meiotic program of male germ cells

Area of Science:

• Reproductive Biology
• Developmental Biology
• Molecular Endocrinology

Background:

• The regulation of meiosis initiation during male spermatogenesis is not fully understood.
• Retinoic acid (RA) is known to induce meiosis in female gonads, but its role in male meiosis is less clear.

Purpose of the Study:

• To investigate the mechanisms by which all trans retinoic acid (ATRA) and Kit Ligand (KL) influence meiotic entry in postnatal mouse spermatogonia.
• To elucidate the signaling pathways involved in ATRA- and KL-induced meiotic progression.

Main Methods:

• In vitro culture of postnatal mouse spermatogonia.
• Treatment with ATRA and KL.
• Analysis of gene expression (Stimulated by Retinoic Acid Gene 8, Dmc1, Kit).
• Use of a Kit tyrosine kinase inhibitor.
• Assessment of PI3K and MAPK pathway activation.

Main Results:

• ATRA and KL independently increase meiotic entry of spermatogonia.
• Spermatogonial competence for meiosis requires Kit-dependent divisions.
• ATRA upregulates Kit in spermatogonia and KL in Sertoli cells.
• Both factors increase expression of meiotic markers (Stimulated by Retinoic Acid Gene 8, Dmc1).
• Kit signaling is essential for ATRA- and KL-induced meiotic entry.
• Meiotic entry is mediated by PI3K and MAPK activation via Kit autophosphorylation.
• ATRA-induced phosphorylation occurs through a non-genomic mechanism.

Conclusions:

• RA controls male meiotic timing by acting on both somatic (Sertoli cells) and germ cells (spermatogonia) via the KL/Kit system.
• The KL/Kit pathway is a central regulator of meiotic entry in postnatal male germ cells.
• Non-genomic mechanisms are involved in RA signaling during spermatogenesis.