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Prepubertal Human Spermatogonia and Mouse Gonocytes Share Conserved Gene Expression of Germline Stem Cell Regulatory Molecules

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Prepubertal Human Spermatogonia and Mouse Gonocytes Share Conserved Gene Expression of Germline Stem Cell Regulatory Molecules Prepubertal human spermatogonia and mouse gonocytes share conserved gene expression of germline stem cell regulatory molecules Xin Wua, Jonathan A. Schmidta, Mary R. Avarbocka, John W. Tobiasb, Claire A. Carlsonc, Thomas F. Kolond, Jill P. Ginsbergc, and Ralph L. Brinstera,1 aDepartment of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104; bPenn Bioinformatics Core, University of Pennsylvania, Philadelphia, PA 19104; and cDivision of Oncology and dDepartment of Urology, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104 Contributed by Ralph L. Brinster, October 30, 2009 (sent for review October 8, 2009) In the human testis, beginning at Ϸ2 months of age, gonocytes are robust methods were developed for rodent germ cell transplan- replaced by adult dark (Ad) and pale (Ap) spermatogonia that make tation and SSC culture conditions (1, 4–8). These techniques led up the spermatogonial stem cell (SSC) pool. In mice, the SSC pool to the characterization of many aspects of SSC biology, including arises from gonocytes Ϸ6 days after birth. During puberty in both the identification of glial cell line-derived neurotrophic factor species, complete spermatogenesis is established by cells that (GDNF) as the main regulator of rodent SSC self-renewal (7, 8). differentiate from SSCs. Essentially pure populations of prepuber- GDNF binds to the c-Ret receptor tyrosine kinase (RET) in tal human spermatogonia and mouse gonocytes were selected combination with the cofactor GDNF-family receptor ␣1 from testis biopsies and validated by confirming the presence of (GFR␣1) to initiate intracellular signaling in SSCs (7, 9, 10). specific marker proteins in cells. Stem cell potential of germ cells Using SSC culture and transplantation in conjunction with was demonstrated by transplantation to mouse testes, following combinations of GDNF withdrawal, microarray analysis, small which the cells migrated to the basement membrane of the interference RNA (siRNA), and signaling molecule inhibition, seminiferous tubule and were maintained similar to SSCs. Differ- several GDNF-regulated genes involved in SSC self-renewal ential gene expression profiles generated between germ cells and were identified and studied in the mouse, including B-cell testis somatic cells demonstrated that expression of genes previ- CLL/lymphoma 6, member B (Bcl6b), Ets variant gene 5 (Etv5), ously identified as SSC and spermatogonial-specific markers (e.g., and LIM homeobox 1 (Lhx1) (10). Three additional GDNF- zinc-finger and BTB-domain containing 16, ZBTB16) was greatly regulated genes, basic helix–loop–helix family, member e 40 elevated in both human spermatogonia and mouse gonocytes (Bhlhb2), homeobox C4 (Hoxc4), and Tec protein tyrosine compared to somatic cells. Several genes were expressed at sig- kinase (Tec) were validated in rat SSCs (11). Among these six nificantly higher levels in germ cells of both species. Most impor- genes, Bcl6b and Etv5 have now been identified as important by tantly, genes known to be essential for mouse SSC self-renewal several studies and appear to play a central role in rodent SSC (e.g., Ret proto-oncogene, Ret; GDNF-family receptor ␣1, Gfr␣1; self-renewal (10–13). GDNF also regulates downstream signal- and B-cell CLL/lymphoma 6, member B, Bcl6b) were more highly ing and ultimately rodent SSC maintenance and self-renewal, expressed in both prepubertal human spermatogonia and mouse which involves phosphatidylinositol 3-kinase/serine-threonine gonocytes than in somatic cells. The results indicate remarkable kinase AKT family (PI3K/AKT), and Src family kinase (SFK) conservation of gene expression, notably for self-renewal genes, in signaling mechanisms (14–16). In contrast to rodent SSCs, little these prepubertal germline cells between two species that di- is known regarding the mechanisms regulating primate SSC verged phylogenetically Ϸ75 million years ago. function. This lack of knowledge is in part due to the absence of techniques for identification and isolation of essentially pure mouse spermatogonia ͉ spermatogenesis populations of primate SSCs for in vitro study. Several groups have attempted to characterize gene expression in human testes. permatogonial stem cells (SSCs) are the foundation for However, the lack of purified cell populations made interpre- Sspermatogenesis and are capable of both self-renewal and tation of results difficult (17, 18). production of daughter cells that differentiate into spermatozoa. To develop an understanding of SSCs and their regulation in the During embryonic development, primordial germ cells (PGCs) human germline, essentially pure populations of prepubertal hu- migrate to the genital ridge and subsequently differentiate into man spermatogonia were isolated and their gene expression profile gonocytes (1, 2). Following birth in the mouse, which has a short determined. Parallel studies were performed on mouse gonocytes (Ϸ3 weeks) prepubertal period, gonocytes undergo a transition for comparison, because extensive data exists regarding mouse to SSCs or develop directly to type A1 spermatogonia, an early SSCs and their regulation. Moreover, a similarity in self-renewal differentiation stage, by day six of life (2). However in humans, and survival mechanisms between human and mouse SSCs may which have a long (Ϸ12 years) prepubertal period, the gonocytes exist because transplantation of testis cells from nonrodent species, are gradually replaced in the first 2–3 months by adult dark (Ad) including human, into testes of immunodeficient mice allowed the and adult pale (Ap) spermatogonia that are thought to represent the reserve and active SSC pool, respectively (2, 3). Beginning at about age 5 years, these Ad and Ap spermatogonia undergo a Author contributions: X.W., J.A.S., and R.L.B. designed research; X.W. and M.R.A. per- formed research; C.A.C., T.F.K., and J.P.G. contributed new reagents/analytic tools; X.W., modest activation, particularly to type B spermatogonia, that J.A.S., J.W.T., and R.L.B. analyzed data; and X.W., J.A.S., and R.L.B. wrote the paper. Ϸ represent 10% of total spermatogonia by age 10. During The authors declare no conflict of interest. puberty, the SSCs in both human and mouse provide the Data deposition: The microarray data reported in this paper has been deposited in the foundation, through self-renewal and differentiation to daughter National Center for Biotechnology Information Gene Expression Omnibus (GEO) database, cells, for spermatogenesis and fertility. www.ncbi.nlm.nih.gov/geo (accession no. GSE18914). The study of rodent gonocytes and SSCs was previously 1To whom correspondence should be addressed. E-mail: [email protected]. hampered by the lack of techniques for purification and long- This article contains supporting information online at www.pnas.org/cgi/content/full/ term in vitro maintenance. However, over the past 15 years, 0912432106/DCSupplemental. 21672–21677 ͉ PNAS ͉ December 22, 2009 ͉ vol. 106 ͉ no. 51 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0912432106 Downloaded by guest on September 26, 2021 human spermatogonia and mouse gonocytes present an oppor- tunity to potentially isolate essentially pure populations of human SSCs and mouse gonocytes, which include the immediate precursor of mouse SSCs. To confirm that the large cells located in the seminiferous tubules were indeed prepubertal human spermatogonia and mouse gonocytes, histological sections were stained for charac- teristic germ cell marker proteins. ZBTB16 (previously known as PLZF) (20, 21) is highly expressed in gonocytes and spermato- gonia, including SSCs, but not in later differentiation stages of spermatogenesis, and the protein was found to be strongly immunostained in the large cells in the seminiferous tubules of both human and mouse testes (Fig. 1 C and D). Other charac- teristic spermatogonial proteins also stained in prepubertal human spermatogonia and mouse gonocytes (Fig. S1). In con- trast, GATA-binding protein 4 (GATA4), which is found in Sertoli cells but not germ cells (22), was not present in the large cells (Fig. 1 E and F). These data demonstrate that the large cells in the seminiferous tubules in both species are indeed immature germ cells. Following digestion of the testis tissue to a single cell suspension, immunostaining for the presence of germ cell and Sertoli cell-specific markers confirmed germ cell markers were expressed exclusively in large round cells from both human and Fig. 1. Germ cells in prepubertal human (age 9 years) and mouse testes (age: mouse testes (Fig. S2). GATA4 was not detected in any large 3 days). Histological cross sections of human (A) and mouse (B) testis show cells, and was exclusively found in smaller cells. large cells (arrows) resting near the basement membrane of the seminiferous tubule. Immunohistochemical staining of human and mouse testes with germ Prepubertal Human Spermatogonia and Mouse Gonocytes Can Be cell markers demonstrated that the large round cells (arrows) expressed Selected and Purified from Testis Cell Suspensions. Because of the CELL BIOLOGY ZBTB16, a well-characterized marker of SSCs and spermatogonia (C, human, D, difference in size and morphological characteristics between the mouse). In contrast, the large cells did not express the somatic cell marker immature germ cells and somatic cells, micromanipulation tech- GATA-4 (E, human, F, mouse), which was present in Sertoli cells (arrow heads). niques to select these two cell types from single cell suspensions Negative control images in which
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