Protein-protein interactions involving specific DNA binding domains appear to play a critical role in gene transcription and its regulation. Our working hypothesis is that such regulatory mechanisms exist in both Sertoli cells and meiotic germ cells and mediate transcriptional activation of elements (e.g. STAT-GAS DNA binding complexes) in the promoters of cytokine-responsive genes, thereby influencing critical transitions in phenotypic expression. Our workplan will use both loss- and gain- of function experimental models to address the roles of STAT-4, STAT-6 and the tyrosine kinase JAK3 in meiotic and early haploid gene expression. Using meiotic prophase as a focal point, we will examine whether critical transition points are influenced by the activation and/or inhibition of spermatocyte STAT-DNA binding. In the pre- meiotic, meiotic prophase and early haploid germ cells, we propose to test whether the transcription factors STAT-4 and STAT-6 will define (a) the platform characteristics of the DNA binding complexes formed following a cytokine signal, (b) the potential for transcriptional control of those opioid (e.g. germ cell specific enkephalin promoter) and meiotic genes (e.g. synaptonemal complex) whose promoters contain functional and distinctive STAT-binding elements and, (c) molecular mechanism(s) mediating the paracrine interactions between germ cells and Sertoli cells (e.g. somatic cell enkephalin promoter and opioid receptors) in a stage-specific manner. Studies proposed in Specific Aims 1 and 3 will test the hypothesis that interleukin-12, interleukin-4, and interferon- alpha/gamma represent both positive and negative autocrine/paracrine cues that influence meiotic gene expression and progression to the early haploid phenotype. Those studies planned in Specific Aim 2 will characterize the Sertoli cell- specific mechanisms that mediate the paracrine interactions subserved by interleukin and opioid growth factors. We anticipate that the results of our studies will identify and further characterize novel transcription factors involved in the regulation of meiosis in the male germ line. The testis represents a unique system in which to delineate the consequences of JAK3 tyrosine phosphorylation, cell-to-cell signalling via interleukin-4 and interleukin-12 during development, and the distinct roles of STAT-4 and STAT-6 in gene transcription, providing mechanistic insight that ma also be relevant to lymphocyte development and immune disorders.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD029428-08
Application #
6526941
Study Section
Special Emphasis Panel (ZRG1-MET (01))
Program Officer
Rankin, Tracy L
Project Start
1995-08-01
Project End
2004-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
8
Fiscal Year
2002
Total Cost
$300,108
Indirect Cost
Name
Population Council
Department
Type
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10017
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
Vigodner, Margarita; Ishikawa, Tomomoto; Schlegel, Peter N et al. (2006) SUMO-1, human male germ cell development, and the androgen receptor in the testis of men with normal and abnormal spermatogenesis. Am J Physiol Endocrinol Metab 290:E1022-33
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
Falender, Allison E; Freiman, Richard N; Geles, Kenneth G et al. (2005) Maintenance of spermatogenesis requires TAF4b, a gonad-specific subunit of TFIID. Genes Dev 19:794-803
Zhang, D; Penttila, T L; Morris, P L et al. (2001) Cell- and stage-specific high-level expression of TBP-related factor 2 (TRF2) during mouse spermatogenesis. Mech Dev 106:203-5
Guo, X; Morris, P; Gudas, L (2001) Follicle-stimulating hormone and leukemia inhibitory factor regulate Sertoli cell retinol metabolism. Endocrinology 142:1024-32
Jenab, S; Morris, P L (2000) Interleukin-6 regulation of kappa opioid receptor gene expression in primary sertoli cells. Endocrine 13:5-Nov
Boffa, L C; Scarfi, S; Mariani, M R et al. (2000) Dihydrotestosterone as a selective cellular/nuclear localization vector for anti-gene peptide nucleic acid in prostatic carcinoma cells. Cancer Res 60:2258-62
Hakovirta, H; Yan, W; Kaleva, M et al. (1999) Function of stem cell factor as a survival factor of spermatogonia and localization of messenger ribonucleic acid in the rat seminiferous epithelium. Endocrinology 140:1492-8

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