Normal fertility in the male requires the constant production of large numbers of gametes over a long time period. Spermatogenesis is a very complex, highly organized and regulated process that involves mitosis, meiosis and unique pathways of differentiation. In general, spermatogenesis involves three major biological fundamentals: (a) the renewal of stem cells and the production and expansion of progenitor cells (mitosis) (b) the reduction, by one-half, of the chromosome numbers in progenitor cells (meiosis) and (c) the unique differentiation of haploid cells (spermiogenesis). Early progenitor cells or spermatogonia are defined as “undifferentiated” or A spermatogonia in the mouse. Once the spermatogonia enter the “differentiation” pathway they begin the series of differentiation steps leading to meiosis and spermiogenesis. The endocrine regulation of spermatogenesis occurs by the interplay of gonadotropins and steroids with the somatic cells of the seminiferous tubules (Sertoli cell and Leydig cells) and of vitamin A directly with the germinal cells.
The research in my laboratory has been directed towards the understanding of mammalian spermatogenesis at the molecular level. Our current studies are focused on the role of vitamin A in this process. In particular we are interested in the mechanisms by which retinoic acid (vitamin A) influences the commitment of germ cells to enter meiosis. These mechanisms are central to the timing of sperm production and the organization of gametogenesis.
In our initial approach we developed extensive mRNA and microRNA expression data bases for both germ cells and somatic cells in the testis using array technology and we are currently enhancing that information using next generation sequencing. Our databases cover nearly all aspects of spermatogenesis including cell specific expression and hormone responsive transcription and are used by investigators worldwide. Our latest emphasis has been on discovering the genes expressed in germ cells that enable the entry of these cells into meiosis. We then examine the role of these genes using a variety of genetic approaches with transgenic mice. The projects span the disciplines from biochemistry to genetics to cell biology.
Koubova, J., et al. (2014). "Retinoic acid activates two pathways required for meiosis in mice." PLoS Genet 10(8): e1004541.
Griswold, M. D. and J. M. Oatley (2013). "Concise review: Defining characteristics of mammalian spermatogenic stem cells." Stem Cells 31(1): 8-11.
Hogarth, C. A. and M. D. Griswold (2013). "Retinoic acid regulation of male meiosis." Curr Opin Endocrinol Diabetes Obes 20(3): 217-223.
Sanz, E., et al. (2013). "RiboTag analysis of actively translated mRNAs in Sertoli and Leydig cells in vivo." PLoS One 8(6): e66179.
Hogarth, C., Evanoff, R., Mitchell, D., Kent, T., Small. C., Amory, J. and Griswold, M. (2013) Turning a spermatogenic wave into a tsunami: synchronizing spermatogenesis using WIN 18,446. Biol Reprod. 2013 PMID 23284139
Tong, M., Yang, Y., Davis, J. and Griswold, M. (2012) Retinol dehydrogenase 10 is indispensible for spermatogenesis in juvenile males. PNAS Proc Natl Acad Sci U S A. 2013 Jan 8;110(2):543-8Epub 2012 Dec 24. PMID: 23267101
Griswold, M. . Hogarth, C. Bowles, J. and Koopman, P.(2012) Initiating Meiosis: The Case for Retinoic Acid Biol Reprod 14;86:35 E Pub before print Nov. 10.PMID: 22075477
Hogarth CA, Evanoff R, Snyder E, Kent T, Mitchell D, Small C, Amory JK, Griswold MD. (2011) Suppression of Stra8 expression in the murine gonad by WIN 18,446 Biol Reprod 84:957-965. Jan 5 (Epub ahead of print) PMID:21209416
Hogarth, C. A., J. K. Amory, et al. (2011). "Inhibiting vitamin A metabolism as an approach to male contraception." Trends in endocrinology and metabolism: TEM 22(4): 136-144.
Hogarth, C. A., R. Evanoff, et al. (2011). "Suppression of Stra8 Expression in the Mouse Gonad by WIN 18,446." Biology of reproduction. [epub]
Snyder, E. M., J. C. Davis, et al. (2011). "Exposure to Retinoic Acid in the Neonatal but Not Adult Mouse Results in Synchronous Spermatogenesis." Biology of reproduction. [epub]
Tong, M. H., D. Mitchell, et al. (2011). "Expression of Mirlet7 Family MicroRNAs in Response to Retinoic Acid-Induced Spermatogonial Differentiation in Mice." Biology of reproduction. [epub]
Zhou, W., G. Wang, et al. (2011). "Gene expression alterations by conditional knockout of androgen receptor in adult Sertoli cells of Utp14b jsd/jsd (jsd) mice." Biology of reproduction 84(2): 400-408.
Amory, J. K., C. H. Muller, et al. (2011). "Suppression of spermatogenesis by bisdichloroacetyldiamines is mediated by inhibition of testicular retinoic acid biosynthesis." Journal of andrology 32(1): 111-119.
Matson, C. K., M. W. Murphy, et al. (2010). "The mammalian doublesex homolog DMRT1 is a transcriptional gatekeeper that controls the mitosis versus meiosis decision in male germ cells." Developmental cell 19(4): 612-624.
Roy Choudhury, D., C. Small, et al. (2010). "Microarray-based analysis of cell-cycle gene expression during spermatogenesis in the mouse." Biology of reproduction 83(4): 663-675.
Snyder, E. M., C. Small, et al. (2010). "Retinoic acid availability drives the asynchronous initiation of spermatogonial differentiation in the mouse." Biology of reproduction 83(5): 783-790.
Zhou, W., G. Wang, et al. (2010). "Gene expression alterations by conditional knockout of androgen receptor in adult sertoli cells of Utp14b(jsd/jsd) (jsd) mice." Biology of reproduction 83(5): 759-766.
Snyder, E. M., C. L. Small, et al. (2010). "Gene expression in the efferent ducts, epididymis, and vas deferens during embryonic development of the mouse." Dev Dyn 239(9): 2479-2491.
Hogarth, C. A. and M. D. Griswold (2010). "The key role of vitamin A in spermatogenesis." J Clin Invest 120(4): 956-962.
Zheng, P., M. D. Griswold, et al. (2010). "Predicting meiotic pathways in human fetal oogenesis." Biol Reprod 82(3): 543-551.
Li, Y., Q. Zhou, R. Hively, L. Yang, C. Small, and M.D. Griswold, "Differential gene expression in the testes of different murine strains under normal and conditions." J Androl, 2009. 30(3): p. 325-37.
Snyder, E.M., C. Small, Y. Li, and M.D. Griswold, "Regulation of Gene Expression by Estrogen and Testosterone in the Proximal Mouse Reproductive Tract." Biol Reprod, 2009.
Houmard, B., C. Small, L. Yang, T. Naluai-Cecchini, E. Cheng, T. Hassold, and M. Griswold, "Global gene expression in the human fetal testis and ovary." Biol Reprod, 2009. 81(2): p. 438-43.
Zhou, Q., Y. Li, R. Nie, P. Friel, D. Mitchell, R.M. Evanoff, D. Pouchnik, B. Banasik, J.R. McCarrey, C. Small, and M.D. Griswold, "Expression of stimulated by retinoic acid gene 8 (Stra8) and maturation of murine gonocytes and spermatogonia induced by retinoic acid in vitro." Biol Reprod, 2008. 78(3): p. 537-45.
Zhou, Q., R. Nie, Y. Li, P. Friel, D. Mitchell, R.A. Hess, C. Small, and M.D. Griswold, "Expression of stimulated by retinoic acid gene 8 (Stra8) in spermatogenic cells induced by retinoic acid: an in vivo study in vitamin A-sufficient postnatal murine testes." Biol Reprod, 2008. 79(1): p. 35-42.
Doyle, T.J., K.W. Braun, D.J. McLean, R.W. Wright, M.D. Griswold, and K.H. Kim, "Potential functions of retinoic acid receptor A in Sertoli cells and germ cells during spermatogenesis." Ann N Y Acad Sci, 2007. 1120: p. 114-30.
Koubova J, Menke DB, Zhou Q, Capel B, Griswold MD, Page DC. 2006 Retinoic acid regulates sex-specific timing of meiotic initiation in mice. Proc Natl Acad Sci USA. 103(8):2474-9.
Lee, T.H., W. Yi, M.D. Griswold, F. Zhu, and C. Her, "Formation of hMSH4-hMSH5 heterocomplex is a prerequisite for subsequent GPS2 recruitment." DNA Repair (Amst), 2006. 5(1): p. 32-42.
Meng J, Holdcraft RW, Shima JE, Griswold MD, Braun RE. 2005 "Androgens regulate the permeability of the blood-testis barrier." Proc Natl Acad Scie USA. 102(46):16696-700.
Hardy, M. and M. Griswold, "Synopsis: XVIIIth Testis Workshop, 'Testicular Cell Dynamics and Endocrine Signaling'". J Androl, 2005. 26(6): p. 675-7.
Li, Y., C.A. Putnam-Lawson, H. Knapp-Hoch, P.J. Friel, D. Mitchell, R. Hively, and M.D. Griswold, "Immunolocalization and regulation of cystatin 12 in mouse testis and epididymis." Biol Reprod, 2005. 73(5): p. 872-80.
Small, C.L., J.E. Shima, M. Uzumcu, M.K. Skinner, and M.D. Griswold, "Profiling gene expression during the differentiation and development of the murine embryonic gonad." Biol Reprod, 2005. 72(2): p. 492-501.
Zhou, Q., J.E. Shima, R. Nie, P.J. Friel, and M.D. Griswold, "Androgen-regulated transcripts in the neonatal mouse testis as determined through microarray analysis." Biol Reprod, 2005. 72(4): p. 1010-9.