Role of development signaling pathways in testicular physiology and spermatogenesis

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Testosterone, the male reproductive hormone, is necessary for normal development, the initiation of puberty and sperm cell production in the testes in all mammalian species. Inadequate testosterone production has a range of negative consequences, such as undescended testes, pseudohermaphroditism and infertility. Although it has long been known that testosterone production by the testicular Leydig cells is stimulated by pituitary luteinizing hormone (LH), our understanding of how this regulatory process works at a molecular level remains very rudimentary. Our group has uncovered strong preliminary evidence to suggest that Hippo, an intracellular signaling pathway traditionally associated with embryonic development, is activated following LH binding. Hippo signaling then acts to suppress the activity of Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), two signaling molecules that seem to block the transcription of genes involved in testosterone synthesis. In the present proposal, we will confirm our preliminary findings and identify the key players within the Hippo pathway that act downstream of LH. The effects of YAP and TAZ on the activity of steroidogenic genes will be studied in detail. Finally, we will create transgenic mice in which critical Hippo pathway genes will be deleted in their Leydig cells, and we will study the consequences of their deletion on testosterone production, steroidogenic gene expression, spermatogenesis and fertility. Taken together, these studies should unearth previously unsuspected mechanisms of regulation of testosterone synthesis, and may provide insight into both the etiology and potential therapies for testosterone insufficiency.