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.