Received: 13 April, 2007. Accepted: 1 August, 2007. Invited Review Functional Development and Embryology ©2007 Global Science Books Mammalian Spermatogenesis Joachim Wistuba * • Jan-Bernd Stukenborg • C. Marc Luetjens Institute of Reproductive Medicine of the University Münster; Domagkstrasse 11, 48129 Münster, Germany Corresponding author: * Joachim.Wistuba@ukmuenster.de ABSTRACT The formation of mature spermatozoa is one of the most essential functions in life. A concerted sequence of events is needed to proliferate, maintain and mature germ cells starting with spermatogonial stem cells and culminating in mature gametes. Apart from the genetic background, this process requires highly organized tissue in which the complex process of spermatogenesis is strongly regulated by hormonal interplay, differential gene expression and cell-cell communication. Although similar overall principles of spermatogenesis are found in all mammalian testes in a much conserved pattern, numerous species-specific features such as efficiency and seasonality determine differences between the various mammals. In this article, we focus on morphological principles as well as on endocrine regulation and action of selected genes. Furthermore we report on recent experiments addressing the fate and physiology of spermatogonial stem cells, testis biology and development of the germ line and the somatic part of the testis by germ line transplantation and in vitro approaches. _____________________________________________________________________________________________________________ Keywords: endocrine regulation, germ cell culture, germ line transplantation, testicular topography, testis Abbreviations: AMH, anti-muellerian-hormone; AR, androgen receptor; CDH-1, formerly known as E-cadherin; CG, chorionic gonadotropin; CREM, cAMP response element modulator; DAZ, deleted in azoospermia; DAZL, deleted in azoospermia like; ERM, Ets related molecule; ES cells, embryonic stem cells; FACS, fluorescence activated cell sorting; FSH, follicle-stimulating hormone; FSHR, follicle-stimulating hormone receptor, GDNF, glia cell line-derived neurotrophic factor; GFR1, GDNF family receptor alpha 1; GnRH, gonadotropin-releasing-hormone; GPR54, G-protein-coupled receptor 54; JSD, juvenile spermatogonial depletion; LH, luteinizing hormone; LHR, luteinizing hormone receptor; LIF, leukaemia inhibiting factor; MACS, magnetic activated cell sorting; PGC, primor- dial germ cells; PR, progesterone receptor; SACS, soft agar culture system; SCF, stem cell factor; SCO, Sertoli cell only syndrome; SRY, sex-determining region Y; SSC, spermatogonial stem cell; TP, transition proteins CONTENTS INTRODUCTORY REMARKS.................................................................................................................................................................... 99 SEXES ARE DIFFERENT: OOGENESIS VS. SPERMATOGENESIS ..................................................................................................... 100 THE MEANING OF SPERMATOGENESIS: PROTECTION OF GENOMIC INTEGRITY DURING GAMETE PRODUCTION....... 101 GENE EXPRESSION AND SPERMATOGENESIS .................................................................................................................................. 102 Arrested spermatogenesis is correlated to failure of gene expression ..................................................................................................... 102 TESTICULAR PRINCIPLES: TOPOGRAPHY OF THE SEMINIFEROUS EPITHELIUM AND SPERMATOGENIC EFFICIENCY. 104 Testicular topography ............................................................................................................................................................................. 104 Spermatogenic stages, spermatogonia and clonal size ............................................................................................................................ 104 ENDOCRINE REGULATION -A COMPLEX CONCERT OF HORMONE ACTION ............................................................................. 106 Kisspeptin, GnRH, Inhibin, FSH and LH ............................................................................................................................................... 106 Androgens and gestagens ....................................................................................................................................................................... 108 TRANSPLANTATION OF THE GERM LINE: MATURATION OF MALE GAMETES AWAY FROM HOME .................................... 110 UNDERSTANDING SPERMATOGENESIS IN VITRO: LESSONS FROM GERM CELL CULTURE ................................................... 111 ACKNOWLEDGEMENTS ........................................................................................................................................................................ 113 REFERENCES............................................................................................................................................................................................ 113 _____________________________________________________________________________________________________________ INTRODUCTORY REMARKS Spermatogenesis is defined as the process of male gamete production. The site of spermatogenesis is the male gonad, the testis. Therefore, spermatogenesis summarizes all events that transform basic spermatogonia into highly speci- alized mature spermatozoa within the testis. Spermatogonia derive from primordial germ cells (PGCs) which, after entering the testis, develop into gonocytes. After spermato- genesis spermatozoa migrate from the testis into the epidi- dymis where they are prepared to reach and fertilize eggs, and transfer the paternal genomic information to the next generation. In the testis, the germ cells are located in tubules of which their inner side is covered by the seminiferous epi- thelium containing somatic Sertoli cells which provide nourishment and support cells of the germ line. Before a gamete can leave the testis, it has to pass through several stages of maturation. These processes include mitotic multi- plication and propagation of the spermatogonial stem cells (SSCs), meiotic recombination of genetic material and testi- cular maturation of spermatozoa (Ehmcke et al. 2006). Several developmental stages of germ cells are distin- guished of which the haploidization of the genome is the major event, the meiotic division. In the fully developed mammalian testis, the majority of undifferentiated cells of the germ line are type A spermatogonia. This population of cells also includes the SSCs. These are the most important