Skinner Laboratory

Testis Research

The proposed research is designed to develop a better understanding of the molecular and cellular mechanisms that control testis development. The integration of critical transcriptional events and cellcell interactions that regulate testis morphogenesis and growth, which directly influences male fertility and sperm production, are of particular interest. Research during the previous grant period demonstrated critical transcription factors appear to regulate the expression of paracrine growth factors to directly influence testis development and male sex determination. THE GENERAL HYPOTHESIS EXAMINED IS THAT CRITICAL TRANSCRIPTIONAL EVENTS DURING GONADAL SEX DETERMINATION REGULATE LOCALLY PRODUCED PARACRINE GROWTH FACTORS THAT ARE ESSENTIAL FOR CELL GROWTH AND DIFFERENTIATION DURING EMBRYONIC AND POSTNATAL TESTIS DEVELOPMENT, AND THAT THIS DIRECTLY INFLUENCES MALE FERTILITY AND SPERM PRODUCTION IN THE ADULT. Abnormal testis development and male infertility may in part be due to inappropriate control of testicular cell differentiation and cell-cell interactions during embryonic development. THE SPECIFIC HYPOTHESIS TESTED IS THAT SUBSEQUENT TO GENETIC MALE SEX DETERMINATION (e.g. SRY) CRITICAL TRANSCRIPTION FACTORS (i.e. SOX9 AND THE BHLH FACTOR TCF21) ARE EXPRESSED IN PRECURSOR SERTOLI CELLS TO PROMOTE THE PRODUCTION OF CRITICAL PARACRINE GROWTH FACTORS (e.g. NT3 AND JAG1) THAT INDUCE TESTIS MORPHOGENESIS (i.e. CORD FORMATION) AND CELL-CELL INTERACTIONS REQUIRED FOR EMBRYONIC TESTIS DEVELOPMENT AND ADULT MALE FERTILITY. Research during the previous grant period indicates that SRY and SOX9 can transcriptionally regulate the Sertoli cell expression of the neurotrophin NT3 which has a critical role in the morphogenesis of the testis (i.e. cord formation). Preliminary studies also indicate that the basic helix-loop-helix (bHLH) family of transcription factors (e.g. TCF21) appear to be important for gonadal development and precursor Sertoli cell differentiation. Further analysis of how these transcriptional events integrate with the growth factor mediated cell-cell interactions to control testis development is the focus of the current proposal and involves the following specific aims: 1. Investigate the role of growth factors on testis morphogenesis and development. 2. Investigate the interactions between SRY/SOX9 and bHLH factors (i.e. TCF21) in the transcriptional regulation of growth factor expression. 3. Investigate the physiological functions of these growth factors during testis development on cell fate and differentiation, as well as testis spermatogenic capacity. The completion of these studies will provide insight into the cell-cell interactions and factors that control embryonic testis growth and function. Abnormal control of these factors and cell-cell interactions during embryonic development are anticipated to result in adult male infertility. Therefore, observations from the current proposal will lead to the design of future preventative or therapeutic treatments of male infertility.

Skinner Laboratory, PO Box 644234, Washington State University, Pullman WA 99164-4234, 509-335-1524, Contact Us