The male reproductive system is essential for sperm production, maturation, and transport, as well as hormonal regulation. The rete testis, a crucial structure within the testis, connects seminiferous tubules to efferent ducts. Defects in its formation can disrupt sperm transport, leading to obstructive azoospermia and male infertility. Despite its critical function, the rete testis remains understudied. Any defects in its development can impair sperm transport, leading to obstructive azoospermia and male infertility.

This project seeks to unravel the molecular mechanisms governing rete testis formation, with a particular focus on the PAX8/SOX9/WNT4 regulatory triad. We recently identified a novel population of supporting-like cells (SLCs) in the developing testis of both mice and humans. These cells arise at the interface between the undifferentiated gonad and the adjacent mesonephros and give rise to the rete testis. However, their specification, differentiation, and maintenance remain poorly understood. We hypothesize that PAX8, SOX9, and WNT4 form a regulatory network that drives SLC specification and rete testis development, ensuring normal male fertility.

To explore the in vivo role of the PAX8/SOX9/WNT4 network, we will:

1.      Characterize gene regulatory networks associated with SLC differentiation.

2.      Utilize mouse models with loss-of-function (LoF) or gain-of-function (GoF) mutations in these key genes.

Our findings will provide crucial insights into variations in sexual development (VSD) and male infertility, conditions that often remain unresolved. A deeper understanding of rete testis formation and function will have significant physiological and clinical implications, aiding in the diagnosis and treatment of fertility disorders.

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In mammals, gonadal sex determination is governed by finely balanced gene expression programs and signaling pathways that drive testicular or ovarian development. Disruptions in this balance can result in differences/disorders of sex development (DSD). Understanding the regulatory mechanisms underlying these antagonistic programs is essential for elucidating both normal gonadal development and the origins of DSDs, many of which remain poorly characterized.

Current research on gonadal development and DSDs primarily focuses on how mutations in protein-coding sequences or cis-regulatory elements (e.g., promoters and enhancers) affect the expression and function of key genes involved in testis and ovary formation. While these studies often emphasize transcriptomic-level gene expression, there is frequently a lack of correlation between mRNA levels and protein production, suggesting that post-transcriptional regulatory mechanisms may play a more significant role than previously appreciated.

.We aim to comprehensively characterize the roles of post-transcriptional modifications, including alternative splicing, RNA methylation, and translational regulation, in gonadal sex determination, using both mouse models and human samples.