title: Loss of Gata4 in Sertoli cells impairs the spermatogonial stem cell niche and causes germ cell exhaustion by attenuating chemokine signaling.
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.
authors.affiliation: State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, RP China.
authors.forename: Su-Ren
authors.initials: SR
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, RP China.|University of the Chinese Academy of Sciences, Beijing, RP China.
authors.forename: Ji-Xin
authors.initials: JX
authors.lastname: Tang
authors.affiliation: State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, RP China.|University of the Chinese Academy of Sciences, Beijing, RP China.
authors.forename: Jin-Mei
authors.initials: JM
authors.lastname: Cheng
authors.affiliation: State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, RP China.|University of the Chinese Academy of Sciences, Beijing, RP China.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, RP China.|University of the Chinese Academy of Sciences, Beijing, RP China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Jin
authors.affiliation: State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, RP China.|University of the Chinese Academy of Sciences, Beijing, RP China.
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Li
authors.affiliation: State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, RP China.
authors.forename: Shou-Long
authors.initials: SL
authors.lastname: Deng
authors.affiliation: State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, RP China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, RP China.
authors.forename: Xiu-Xia
authors.initials: XX
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, RP China.
authors.forename: Yi-Xun
authors.initials: YX
authors.lastname: Liu
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D002454:Cell Differentiation; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D019742:Chemokines, CC / Q000235:genetics / Q000378:metabolism*; D002633:Chemotaxis; D005260:Female; D050991:GATA4 Transcription Factor / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D019402:Macrophage Inflammatory Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012708:Sertoli Cells / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction; D013091:Spermatogenesis; D013093:Spermatogonia / Q000378:metabolism / Q000473:pathology*; D055153:Stem Cell Niche; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology*
chemical_list: C095218:Ccl9 protein, mouse; D054377:Chemokine CXCL12; D019742:Chemokines, CC; C515256:Cxcl12 protein, mouse; D050991:GATA4 Transcription Factor; C484171:Gata4 protein, mouse; D019402:Macrophage Inflammatory Proteins; D012333:RNA, Messenger; D008156:Luciferases
keywords: Gata4; Pathology Section; Sertoli cells; chemokines; niche; spermatogonial stem cell