Francisco J. Diaz

Research

Female germ cell development occurs in the context of an ovarian follicle, which contains a germ cell (oocyte or egg) and somatic granulosa and theca cells. Intercommunication between oocytes and granulosa cells is necessary for proper oocyte and follicular development. Research in our laboratory focuses on understanding the molecular and functional interactions between oocytes and granulosa cells that promote production of a fertile oocyte. This knowledge can then be used to (1) develop better therapeutic interventions for infertility or species preservation and (2) develop better reproductive management tools for animal agriculture.

Interaction between oocytes and granulosa cells

It is well established that the bi-directional interaction between the oocyte and the surrounding granulosa cells is vitally important for oocyte and granulosa cell development. Members of the TGF-beta superfamily of signaling molecules are produced by both oocytes and granulosa cells and are indispensable for promoting oocyte and follicular development. These secreted molecules act by binding to cell surface receptors and activating SMAD proteins, which then influence gene transcription. Our laboratory uses transgenic technology and in vitro culture to uncover how SMAD-mediated signaling and other signaling pathways regulate oocyte growth and development. In addition, we are developing co-culture systems to examine the reciprocal relationship between oocytes and granulosa cells in birds using genomic and proteomic technology. Our objective is to isolate secreted products from mammalian and avian follicles that impact oocyte development and fertility.

Role of zinc in oocyte and follicular development.

Zinc is an essential nutrient needed for a plethora of cellular and biological processes. We have uncovered an important role for dietary zinc during the immediate preovulatory period for the normal formation of the meiotic spindle and progression through meiosis to metaphase II.  Intriguingly, lack of preconception dietary zinc also alters epigenetic programming of the oocyte such that both fetal and placental development are impaired later in pregnancy. In somatic cells of the ovary, zinc is required for cumulus expansion and follicle rupture. We are now studying the cellular mechanisms underlying these observations in both oocytes and granulosa cells.

Mechanisms regulating differences in reproductive capacity between broiler-breeder and laying hens.

Genetic selection for growth and development (broilers) has led to a decrease in reproductive efficiency in broiler breeder hens compared to egg-laying hens. However, the mechanisms leading to decreased reproductive efficiency in broiler-breeder hens are unclear. We will determine at the ovarian level the molecular differences between broiler-breeder and laying hens using microarray, cell culture, and biochemical analyses. These molecular differences could then be used as therapeutic targets to increase reproductive efficiency or as selectable markers for breeding management.

Development of novel cellular targets for future contraceptive development.

We are searching for novel contraceptive targets using a high-throughput cellular screen to search for compounds that block oocyte maturation, fertilization and/or cumulus expansion. 

Publications

Sun T and Diaz FJ. Ovulatory signals lead to YAP1-mediated decrease of proliferation and increase of differentiation in mouse granulosa cells. Reproductive Biology and Endocrinology: In press.

Li H, Garner TB, Diaz FJ and Wong PK. A Multiwell Microfluidic Device for Analyzing and Screening Non-Hormonal Contraceptive Agents. Small. 2019 Jul;15(28):e1901910.

Liu WS, Zhao Y, Lu C, Ning G, Ma J, Diaz FJ, and O'Connor M. A novel testis-specific protein, PRAMEY, is involved in spermatogenesis in cattle.  Reproduction (2017) 153 (6), 847-863.

Hester J, Hanna-Rose W and Diaz FJ.  Zinc depletion reduces fertility and disrupts oocyte development in C. elegans.  Comparative Biochemistry and Physiology. (2017) 191, 203-209

Tian X, Anthony K and Diaz FJ.  Transition metal chelator induces progesterone production in mouse cumulus-oocyte complexes and corpora lutea. Biological Trace Mineral Research. (2017) doi:10.1007/s12011-016-0841-x.

Sun T, Pepling ME, Diaz FJ.  Lats1 Deletion Causes Increased Germ Cell Apoptosis and Follicular Cysts in Mouse Ovaries.  Biology of Reproduction (2015)  doi:10.1095/biolreprod.114.118604

Tian X, Anthony K, Neuberger T and Diaz FJ.  Preconception zinc deficiency disrupts postimplantation fetal and placental development.  Biology of Reproduction (2014) 90 (4):83.

Haughian JM, Ginther OJ, Diaz FJ, Wiltbank MC. GnRH, Estradiol, and Inhibin Regulation of FSH and LH Surges: Implications for Follicle Emergence and Selection in Heifers.  Biology of Reproduction (2013) 88(6):165,1-10.

Diaz FJ and Anthony K.  Feed restriction inhibits early follicular development in broiler-breeder hens.  Animal Reproduction (2013) 10(2): 79-87.

Tian X and Diaz FJ.  Acute dietary zinc deficiency before conception compromises oocyte epigenetic programming and disrupts embryonic development. Developmental Biology (2013) 376(1):51-61.

Lisle RS, Anthony K, Randall M and Diaz FJ.  Oocyte-cumulus cell interactions regulate free intracellular zinc in mouse oocytes.  Reproduction (2013) 145: 381-390.

Mistry BV, Zhao Y, Chang TC, Yasue H, Chiba M, Oatley J, Diaz FJ and Liu WS.  Differential Expression of PRAMEL1, a Cancer/Testis Antigen, during Spermiogenesis in the Mouse.  PLOS one: (2013) 8(4): e60611

Diaz FJ, Luo W and Wiltbank MC.  Prostaglandin F2alpha regulation of mRNA for activating protein 1 transcriptional factors in porcine corpora lutea (CL): lack of induction of JUN and JUND in CL without luteolytic capacity. Domestic Animal Endocrinology (2013) 44(2):98-108.

Wiltbank MC, Salih SH, Atli SH, Luo W, Bormann CW, Ottobre JS, Vezina CM, Mehta V, Diaz FJ, Tsai SJ, and Sartori R.  Comparison of endocrine and cellular mechanisms regulating the corpus luteum of primates and ruminants.  Animal Reproduction: (2012) 9(3), 242-259. 

Tian X and Diaz FJ. Zinc depletion causes multiple defects in ovarian function during the periovulatory period. Endocrinology: (2012) 153:873-886.   

Luo W, Diaz F and Wiltbank MC.  Induction of chemokine mRNA and endothelial adhesion molecules by prostaglandin F2alpha is dependent upon stage of the porcine corpus luteum and intraluteal progesterone.  Endocrinology: (2011) 152:2797-2805.

Diaz FJ, Luo W and Wiltbank MC.  Effect of decreasing intraluteal progesterone on sensitivity of the early corpus luteum to the luteolytic actions of prostaglandin F2alpha.  Biology of Reproduction (2011): 84:26-33.

Diaz FJ, Halfhill AN and Anthony K. Early avian follicular development is characterized by changes in transcripts involved in steroidogenesis, paracrine signaling and transcription.  Molecular Reproduction and Development: (2011) 78(3)212-223.

Tian X, Halfhill AN, and Diaz FJ.  Localization of phosphorylated SMAD proteins in granulosa cells, oocytes and oviduct of female mice.  Gene Expression Patterns (2010) 10:105-112.

Diaz FJ, Sugiura K and Eppig JJ.  Regulation of Pcsk6 expression during the preantral to antral follicle transition in mice: opposing roles of FSH and oocytes.  Biology of Reproduction (2008) 78:176-183.

Sugiura K, Su YQ, Diaz FJ, Pangas SA, Sharma S, Wigglesworth K, O'Brien MJ, Matzuk MM, Shimasaki S and Eppig JJ.  Oocyte-derived BMP15 and FGFs cooperate to promote glycolysis in companion cumulus cells.  Development (2007) 134:2593-2603.

Diaz FJ, Wigglesworth K and Eppig JJ.  Oocytes determine cumulus cell lineage in mouse ovarian follicles.  Journal of Cell Science (2007) 120 1330-1340.

Diaz FJ, Wigglesworth K and Eppig JJ.  Oocytes are required for the preantral granulosa cell to cumulus cell transition in mice.  Developmental Biology (2007) 305:300-311.

Diaz FJ, O'Brien M, Wigglesworth K and Eppig JJ.  The preantral granulosa cell to cumulus cell transition: Competence to undergo expansion. Developmental Biology (2006) 299:91-104.

Diaz FJ and Wiltbank MC.  Acquisition of luteolytic capacity: Changes in prostaglandin F2alpha regulation of genes involved in progesterone biosynthesis in the porcine corpus luteum.  Domestic Animal Endocrinology (2005) 28:172-189.

Diaz FJ and Wiltbank MC.  Acquisition of luteolytic capacity:  Changes in prostaglandin F2alpha egulation of steroid hormone receptors and estradiol biosynthesis in pig corpora lutea.   Biology of Reproduction (2004) 70:1333-1339.

Mattos R, Staples CR, Arteche A, Wiltbank MC, Diaz FJ, Jenkins TC and Thatcher WW.  The effects of feeding fish oil on uterine secretion of PGF2alpha, composition, and metabolic status of periparturient holstein cows.  Journal of Dairy Science (2004) 87:921-932.

Diaz FJ, Anderson LE, Wu YL, Rabot A, Tsai SJ and Wiltbank MC.  Regulation of progesterone and prostaglandin production in the CL. Molecular and Cellular Endocrinology (2002) 191:65-80. 

Diaz FJ, Crenshaw TD and Wiltbank MC.  Prostaglandin F2alpha induces distinct physiological responses in porcine corpora lutea after acquisition of luteolytic capacity.  Biology of Reproduction (2000) 63:1504-1512.

Pyeon D, Diaz FJ and Splitter GA.  Prostaglandin E(2) increases bovine leukemia virus tax and pol mRNA levels via cyclooxygenase 2: Regulation by interleukin-2, interleukin-10, and bovine leukemia virus. Journal of Virology (2000) 74:5740-5745.