Abstract
Sertoli cells, the primary somatic cell in the seminiferous epithelium, provide the spermatogonial stem cell (SSC) microenvironment (niche) through physical support and the expression of paracrine factors. However, the regulatory mechanisms within the SSC niche, which is primarily controlled by Sertoli cells, remain largely unknown. GATA4 is a Sertoli cell marker, involved in genital ridge initiation, sex determination and differentiation during the embryonic stage. Here, we showed that neonatal mice with a targeted disruption of Gata4 in Sertoli cells (Gata4(flox/flox); Amh-Cre; hereafter termed Gata4 cKO) displayed a loss of the establishment and maintenance of the SSC pool and apoptosis of both gonocyte-derived differentiating spermatogonia and meiotic spermatocytes. Thus, progressive germ cell depletion and a Sertoli-cell-only syndrome were observed as early as the first wave of murine spermatogenesis. Transplantation of germ cells from postnatal day 5 (P5) Gata4 cKO mice into Kit(W/W-v) recipient seminiferous tubules restored spermatogenesis. In addition, microarray analyses of P5 Gata4 cKO mouse testes showed alterations in chemokine signaling factors, including Cxcl12, Ccl3, Cxcr4 (CXCL12 receptor), Ccr1 (CCL3 receptor), Ccl9, Xcl1 and Ccrl2. Deletion of Gata4 in Sertoli cells markedly attenuated Sertoli cell chemotaxis, which guides SSCs or prospermatogonia to the stem cell niche. Finally, we showed that GATA4 transcriptionally regulated Cxcl12 and Ccl9, and the addition of CXCL12 and CCL9 to an in vitro testis tissue culture system increased the number of PLZF+ undifferentiated spermatogonia within Gata4 cKO testes. Together, these results reveal a novel role for GATA4 in controlling the SSC niche via the transcriptional regulation of chemokine signaling shortly after birth.
Highlights
50% of human infertility is attributable to male defects, of which 70-90% stem from impaired spermatogenesis [1]
As spermatogonial stem cell (SSC) exhibited defects in both establishment and maintenance in Gata4 cKO testes (Figure 3), we examined the fate of the gonocytederived differentiating spermatogonia in Gata4 cKO testes. c-KIT staining of differentiated spermatogonia (Figure 4B) and STRA8 staining of meiotic spermatocytes (Figure 4C) were similar in control and Gata4 cKO testes at P9, suggesting that the differentiation of gonocytederived differentiating spermatogonia was not disrupted by GATA4 deletion in Sertoli cells
Several lines of evidence suggest that the Sertoli cell-enriched transcription factor GATA4 is necessary during multiple stages of embryonic gonad development, including genital ridge formation [27], sex determination [18] and testicular differentiation [21]
Summary
50% of human infertility is attributable to male defects, of which 70-90% stem from impaired spermatogenesis [1]. The process of spermatogenesis can be divided into three phases: mitotic proliferation of spermatogonia, meiotic division of spermatocytes and morphologic differentiation of haploid spermatids during spermiogenesis. Mouse spermatogenesis is initiated only a few days after birth and proceeds in a synchronized manner [2]. Key time points regarding the appearance of particular germ cell types are well defined during the first cycle of spermatogenesis [3, 4]. Postnatal day (P) 5-7 mouse testes contain only Sertoli cells and gonocyte-derived spermatogonia in the seminiferous tubules. Spermatocytes appear at P9, the pachytene stage of the first meiotic prophase is initiated at P14, round spermatids are generated at P20, and condensing spermatids are created by P30 [3, 5]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
