The epididymis, and in particular, the initial segment, play an important role in the maturation of spermatozoa and without a fully developed initial segment, male infertility will result. The central hypothesis of this proposal is that defects in epididymal function arise from abnormal initial segment development and considering that the human epididymis has an initial segment-like epithelium, it is important to understand the development of this region. We are especially interested in understanding the mechanisms that regulate the development of this important organ because disruptions to epididymal function may also arise as a consequence of abnormal development. Therefore, in this application a premium is placed upon understanding the regulation of cell proliferation during development. Although androgens regulate epididymal development, lumicrine factors (testicular luminal fluid factors) are hypothesized to play a major role. This is a novel hypothesis because lumicrine factors have only been associated with protection of the initial segment from undergoing apoptosis. Further, the experiments outlined in the application will challenge the dogma that cell proliferation is not differentially regulated postnatally. Our working hypothesis is that as lumicrine factors switch from regulating cell proliferation postnatally to regulating cell survival in adulthood, cells move from a proliferative state to a non-proliferative state. This is achieved by regulating specific signaling pathways via upstream lumicrine growth factor ligand(s) interacting with their cognate receptors on the apical membrane of initial segment cells, thereby ensuring the formation of a fully developed and proper functioning initial segment. To test this hypothesis, three specific aims are proposed: (1) To test the hypothesis that lumicrine factors regulate initial segment cell proliferation in a window of time during the postnatal period, (2) To test the hypothesis that luminal FGFs and downstream signaling pathways regulate the expression of cell proliferation signal transduction pathways in the postnatal initial segment, (3) To test the hypothesis that the switch between the FGF/FGFR/ PI3K/Akt/mTOR pathway, which is required for cell proliferation, toFGF/FGFR/pERK/pMEK pathway, which is required for cell protection is the result of PTEN upregulation, activation and/or redistribution at a specific stage during initial segment postnatal development. The anticipated outcomes of this study will not only have a major impact on an area of reproductive biology that has been poorly understood, but will also contribute to our understanding of the fundamental process of duct/tube elongation. Specifically they will provide an understanding of how the development of one epididymal specific region is important clinically and how the regulation of growth of the epididymis during development will contribute to our understanding of why the epididymis rarely succumbs to cancer.

Public Health Relevance

Disruption of epididymal function and therefore, male infertility, will arise as a consequence of abnormal fetal development. Therefore, it is important to examine and understand the causes of congenital defects that lead to male infertility. Further, understanding the development and growth of the epididymis will provide fundamental information as to why this organ rarely succumbs to cancer.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
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Moss, Stuart B
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University of Virginia
Anatomy/Cell Biology
Schools of Medicine
United States
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Domeniconi, Raquel F; Souza, Ana Cláudia Ferreira; Xu, Bingfang et al. (2016) Is the Epididymis a Series of Organs Placed Side By Side? Biol Reprod 95:10
Ribeiro, Camilla M; Silva, Erick J R; Hinton, Barry T et al. (2016) ?-defensins and the epididymis: contrasting influences of prenatal, postnatal, and adult scenarios. Asian J Androl 18:323-8
Xu, Bingfang; Washington, Angela M; Hinton, Barry T (2016) Initial Segment Differentiation Begins During a Critical Window and Is Dependent upon Lumicrine Factors and SRC Proto-Oncogene (SRC) in the Mouse. Biol Reprod 95:15
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Xu, Bingfang; Washington, Angela M; Hinton, Barry T (2014) PTEN signaling through RAF1 proto-oncogene serine/threonine kinase (RAF1)/ERK in the epididymis is essential for male fertility. Proc Natl Acad Sci U S A 111:18643-8
Xu, Bingfang; Yang, Ling; Hinton, Barry T (2013) The Role of fibroblast growth factor receptor substrate 2 (FRS2) in the regulation of two activity levels of the components of the extracellular signal-regulated kinase (ERK) pathway in the mouse epididymis. Biol Reprod 89:48