Abnormalities of spermatogenesis often present in testicular biopsies from the infertile male and include germ cell aplasia, maturational arrest or decreased numbers of proliferating and developing germ cells. Since local secretory factors and cell-to-cell associations within the seminiferous tubule create a microenvironment that regulates the progression of spermatogenic events, inappropriate intratesticular signals of both germ and Sertoli cell proliferation may be involved in some types of growth arrests. The rodent testis provides a useful model for studying the intercellular signals of proliferation and differentiation necessary to ensure adequate sperm production and fertilizing capacity. Neuropeptides act as proliferative signals in concert with both growth factors and cytokines in the neural and immune systems. Two of the testicular neuropeptides, the proenkephalin- and prodynorphin-derived opioids are differentially expressed in Sertoli and germ cells. Opioids regulate Sertoli cell proliferation which, in turn, appears to determine the numbers of post- meiotic germ cells undergoing differentiation. Although certain opioids are found associated with the head of spermatozoa and the principal cells of the epididymis, their physiological role in male fertility is presently unknown. Recent studies indicate that signalling pathways between germ and Sertoli cells involve several intratubular factors secreted by both cells including the opioids, growth factors, and interleukins. An exciting new discovery in our laboratory revealed the existence of a novel IL-6 cytokine signalling pathway mediated by the members of the STAT family of transcription factors. Our studies will focus on the unique features of the regulation of the two opioid genes by cell-to-cell interactions. The cell-specific expression of both proenkephalin and prodynorphin and their regulation by germ cell factors will be studied by hybridization in situ and immunohistochemistry. The mechanism(s) of action of the opioid peptides will be investigated using both germinal and somatic cell proliferation and gene expression. A newly identified stage-specific germ cell protein(s) that regulates opioid gene expression in Sertoli cells will be characterized. Cloned cDNAs for the opioid-regulating protein(s) will be isolated and their structure characterized. The cDNA will be subcloned into expression systems to generate recombinant opioid- regulating protein. These goals will ultimately enable us to identify and characterize the germ cell factor(s) which regulates the expression of the two opioid genes Moreover, specific probes will be generated for use in localizing aberrant expression of these opioid-regulating factors in genetically mutant and experimental rodent models of infertility. This research plan will lead to new and significant data on the mechanisms of opioid signalling and its physiological relevance to proliferation and differentiation within the tubule. Characterization of a testicular opioid-regulating factor will facilitate studies to delineate the physiological role of the opioid-derived peptides in normal male reproductive function.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Reproductive Biology Study Section (REB)
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Population Council
New York
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Ishikawa, Tomomoto; Morris, Patricia L (2006) Interleukin-1beta signals through a c-Jun N-terminal kinase-dependent inducible nitric oxide synthase and nitric oxide production pathway in Sertoli epithelial cells. Endocrinology 147:5424-30
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Ishikawa, Tomomoto; Morris, Patricia L (2006) A multistep kinase-based sertoli cell autocrine-amplifying loop regulates prostaglandins, their receptors, and cytokines. Endocrinology 147:1706-16
Ishikawa, Tomomoto; Hwang, Keumsil; Lazzarino, Deborah et al. (2005) Sertoli cell expression of steroidogenic acute regulatory protein-related lipid transfer 1 and 5 domain-containing proteins and sterol regulatory element binding protein-1 are interleukin-1beta regulated by activation of c-Jun N-terminal kinase and cycloo Endocrinology 146:5100-11
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Guo, X; Morris, P; Gudas, L (2001) Follicle-stimulating hormone and leukemia inhibitory factor regulate Sertoli cell retinol metabolism. Endocrinology 142:1024-32
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