Oncotarget

Research Papers: Pathology:

Loss of Gata4 in Sertoli cells impairs the spermatogonial stem cell niche and causes germ cell exhaustion by attenuating chemokine signaling

Su-Ren Chen, Ji-Xin Tang, Jin-Mei Cheng, Jian Li, Cheng Jin, Xiao-Yu Li, Shou-Long Deng, Yan Zhang, Xiu-Xia Wang and Yi-Xun Liu _

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Oncotarget. 2015; 6:37012-37027. https://doi.org/10.18632/oncotarget.6115

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Abstract

Su-Ren Chen1, Ji-Xin Tang1,2, Jin-Mei Cheng1,2, Jian Li1,2, Cheng Jin1,2, Xiao-Yu Li1,2, Shou-Long Deng1, Yan Zhang1, Xiu-Xia Wang1 and Yi-Xun Liu1

1 State key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, RP China

2 University of the Chinese Academy of Sciences, Beijing, RP China

Correspondence to:

Yi-Xun Liu, email:

Keywords: Gata4, spermatogonial stem cell, Sertoli cells, niche, chemokines, Pathology Section

Received: July 30, 2015 Accepted: September 28, 2015 Published: October 14, 2015

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 (Gata4flox/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 KitW/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.


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