ERM is required for transcriptional control of the spermatogonial stem cell niche

Abstract

Division of spermatogonial stem cells 1 produces daughter cells that either maintain their stem cell identity or undergo differentiation to form mature sperm. The Sertoli cell, the only somatic cell within seminiferous tubules, provides the stem cell niche through physical support and expression of surface proteins and soluble factors 2,3 . Here we show that the Ets related molecule 4 (ERM) is expressed exclusively within Sertoli cells in the testis and is required for spermatogonial stem cell self-renewal. Mice with targeted disruption of ERM have a loss of maintenance of spermatogonial stem cell self-renewal without a block in normal spermatogenic differentiation and thus have progressive germ-cell depletion and a Sertoli-cell-only syndrome. Microarray analysis of primary Sertoli cells from ERM-deficient mice showed alterations in secreted factors known to regulate the haematopoietic stem cell niche. These results identify a new function for the Ets family transcription factors in spermatogenesis and provide an example of transcriptional control of a vertebrate stem cell niche.

Gdnf signaling pathways within the mammalian spermatogonial stem cell niche

“…The binding of Gdnf triggers the activation of multiple signaling pathways in responsive cells (Airaksinen and Saarma, 2002). As mentioned previously, Gdnf in the testis is produced by Sertoli cells, which establish the niche in which the SSCs reside (Viglietto et al, 2000;Meng et al, 2000;Meng et al, 2001a), and this activity extends throughout life (Chen et al, 2005). In Sertoli cells, the production of Gdnf is mainly under the influence of FSH, growth factors and cytokines (Tadokoro et al, 2002;Simon et al, 2007).…”

“…Several knockouts targeting transcription factors have recently resulted in mice exhibiting a progressive loss of germ cells leading to adult infertility (Chen et al, 2005;Falender et al, 2005;Buaas et al, 2004;Costoya et al, 2004). One of these factors, Etv5 (Ets Variant Gene 5), belongs to the Pea3 group of the Ets family of proteins, which are characterized by a highly conserved DNA-binding ETS domain (Sharrocks et al, 1997).…”

“…Etv5 is expressed in numerous developing organs of different species (Raible and Brand, 2001;Paratore et al, 2002;Liu et al, 2003;Ouyang et al, 1999), and is over-expressed in several human tumors, in particular breast and endometrial carcinoma (Chotteau-Lelievre et al, 2004;Planaguma et al, 2005). Mice with a targeted disruption of Etv5 (Etv5 -/-) undergo a first wave of spermatogenesis during juvenile life, but show a progressive loss of spermatogenesis, with disappearance of all germ cells and a Sertoli cell-only phenotype by 10 weeks of age (Chen et al, 2005). The initial testicular development in Etv5 -/-mice is similar to that of the wild type, indicating that the major effects of Etv5 deficiency occur postnatally (Schlesser et al, 2007).…”

“…The initial testicular development in Etv5 -/-mice is similar to that of the wild type, indicating that the major effects of Etv5 deficiency occur postnatally (Schlesser et al, 2007). Etv5 is expressed in Sertoli cells and germ cells (Chen et al, 2005;Oatley et al, 2007), but its exact mode of action in both cell types is still unknown. Microarray and RT-PCR analysis of Etv5-/-Sertoli cells detected a 9-to 25-fold reduction in several chemokines and a tenfold reduction in matrix metalloproteinase-12 (MMP-12) expression.…”

GDNF Signaling Regulates YBX1/mRNA Interactions in Mouse Spermatogonia.

“…Sertoli cells, such as ERM, Claudin 11 and Androgen Receptor (AR) [80][81][82]. Furthermore, transplantation of functioning Sertoli cells in a mouse can recover fertility in mice with genetic Sertoli cell defects [83].…”