Stem Cell Niche System in Mouse Spermatogenesis - Male Germline Stem Cells Developmental and Regenerative Potential - page 170

suggested the essential role of GDNF signaling in the maintenance of the stem cell
compartment in vivo rather than its establishment (Meng et al. 2000 ).
This work was a milestone and, following this study, mutations in several genes
have been shown to exhibit similar phenotypes. Some such genes function in the somatic
cells [such as GDNF, Etv5/ERM (see below)], while others function in the germ
cells [such as c-Ret, GFRa1, mUtp14b [mutated in jsd ( juvenile spermatogonial
depletion ) (Beamer et al. 1988 ; Rohozinski and Bishop 2004 ; Bradley et al. 2004 )],
Plzf [mutated in luxoid (Buaas et al. 2004 ; Costoya et al. 2004 )], Taf4b (Falender
et al. 2005 )]. The former group of genes may be involved in the control of the niche
microenvironment. This chapter, which focuses on the stem cell niche , describes the
genes that act in somatic cells in the following sections.
The GDNF ligand is expressed in Sertoli cells, while c-Ret and GFRa1 are
expressed in spermatogonia, namely, in the least matured subsets of A undiff (Hofmann
et al. 2005 ; Tokuda et al. 2007 ). So far, the precise localization of GDNF expression
has not been achieved due to its low expression levels. However, the forced expres-
sion of GDNF in Sertoli cells causes the abnormal accumulation of stem cell-like
spermatogonia with immature phenotypes (Meng et al. 2000 ; Yomogida et al. 2003 ).
These loss-of-function and gain-of-function experiments indicate that GDNF signaling
mediates stem cell regulation by Sertoli cells. Importantly, the identification of
GDNF signaling as an essential factor in vivo has led to the successful establishment
of a spermatogonial culture that retains the stem cell potential by addition of GDNF
ligand and sometimes a soluble form of GFRa1 (Kanatsu-Shinohara et al. 2003 ;
Kubota et al. 2004 ). Altogether, GDNF is crucial for the expansion, survival, and/or
maintenance of spermatogenic stem cells. The downstream cascade of GDNF
signaling would affect the intracellular machinery of the stem cells per se, and this
is one of the current foci of interest in this field (Hofmann 2008 ; Jijiwa et al. 2008 ;
Oatley et al. 2007 ).

8.6.1.2 CSF1 (Colony Stimulating Factor 1/Macrophage

Colony-Stimulating Factor or M-CSF) Signaling

Recently, gene expression profiling has revealed that the receptor for CSF1 (Csf1r)
is highly expressed in candidate stem cell populations (Oatley et al. 2009 ; Kokkinaki
et al. 2008 ). In contrast, the CSF1 (Colony Stimulating Factor 1) ligand is expressed
in Leydig cells and a subset of myoid cells (Oatley et al. 2009 ). The addition of
CSF1 to the GDNF-containing spermatogonial stem cell culture increased the con-
tent of the posttransplantation colony-forming cells (Oatley et al. 2009 ). Although
the in vivo function of this signaling pathway remains to be elucidated, it is
suggested that CSF1 may cooperate with GDNF in supporting the self-maintenance
of stem cells. CSF1 expression in the interstitium suggests that it could be involved
in the function of the vasculature-associated niche, which possibly regulates the
stem cells. Further investigations would be warranted regarding this pathway and
its relationship with GDNF and other signals.