CELL-CELL INTERACTIONS AND TESTIS
DEVELOPMENT
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.