ROS amplification drives mouse spermatogonial stem cell self-renewal.

Area of Science:

• Stem cell biology
• Molecular signaling pathways
• Reproductive biology

Background:

• Reactive oxygen species (ROS) are crucial for stem cell self-renewal, but their integration with self-renewal mechanisms is not fully understood.
• Spermatogonial stem cells (SSCs) are essential for male fertility and rely on precise self-renewal regulation.

Purpose of the Study:

• To elucidate the molecular mechanisms by which ROS signals regulate spermatogonial stem cell (SSC) self-renewal.
• To identify key signaling pathways involved in ROS-mediated SSC self-renewal.

Main Methods:

• Investigated the role of the MAPK14/MAPK7/BCL6B pathway in cultured SSCs.
• Utilized targeted gene deletion of Mapk14 and Mapk7 in mice.
• Performed spermatogonial transplantation assays.
• Analyzed ROS production and gene expression, including Nox1.
• Identified transcription factor targets of MAPK7 and BCL6B.

Main Results:

• The MAPK14/MAPK7/BCL6B pathway forms a positive feedback loop that amplifies ROS to promote SSC self-renewal.
• Deletion of Mapk14 or Mapk7 led to significant SSC deficiency.
• Pathway activation increased Nox1 expression and ROS levels.
• BCL6B initiates ROS production by upregulating Nox1 via ETV5, and is itself activated by ROS.

Conclusions:

• A positive feedback loop involving MAPK14, MAPK7, and BCL6B amplifies ROS signals, driving SSC self-renewal.
• This pathway is critical for maintaining SSC populations and male fertility.
• BCL6B acts as a central regulator, integrating ROS signals to sustain SSC self-renewal.