Genetic Analyses Reveal Functions for MAP2K3 and MAP2K6 in Mouse Testis Determination

Area of Science:

• Developmental Biology
• Genetics
• Molecular Biology

Background:

• Testis determination in mammals is initiated by SRY gene expression in the embryonic gonad.
• Mitogen-activated protein kinase (MAPK) signaling, including MAP3K4 and p38 MAPK, is essential for testis determination.
• The role of MAP2K kinases in sex determination remained largely unexplored despite their position in the MAPK cascade.

Purpose of the Study:

• To investigate the roles of MAP2K3 and MAP2K6 in mammalian testis determination.
• To elucidate the function of MAP2K kinases within the MAPK signaling pathway during embryonic gonadal development.

Main Methods:

• Generation and analysis of knockout mouse models for Map2k3 and Map2k6.
• Utilized compound mutants and a sensitized genetic background (Sry(AKR)) to assess kinase function.
• Evaluated embryonic gonadal development and SRY expression levels at specific developmental time points.

Main Results:

• Loss of MAP2K6 led to complete XY gonadal sex reversal, while MAP2K3 loss showed no significant effect in standard knockout mice.
• Compound mutants exhibited delayed testis determination and transient ovotestis formation, suggesting partially redundant roles.
• On a sensitized background, MAP2K3 loss exacerbated ovotestis development, and MAP2K6 loss caused XY sex reversal with reduced SRY expression.

Conclusions:

• MAP2K6 is critical for mouse testis determination, likely by positively regulating SRY expression.
• MAP2K3 plays a minor, partially redundant role in testis determination alongside MAP2K6.
• These findings identify novel roles for MAP2K kinases in the genetic regulation of mammalian sex determination.