Molecular Mechanisms Regulating Spermatogonial Stem Cell Fate Decisions - Male Germline Stem Cells Developmental and Regenerative Potential - page 146

Mili −/− mice is arrested at early prophase of meiosis during the spermatocyte stage
causing male infertility (Kuramochi-Miyagawa et al. 2004 ). This phenotype
suggests that similar to MIWI, stem cell function in the mouse testis does not
require MILI expression; however, recent studies suggest otherwise and imply a
role in SSC function (Unhavaithaya et al. 2009 ). Examination of testes from both
pre-pubertal and adult Mili −/− mice revealed reduced mitotic activity of the sper-
matogonial population. At 8 days of age, reduced spermatogonial proliferation was
observed in Mili −/− mice, which was considered evidence of impaired SSC prolif-
eration (Unhavaithaya et al. 2009 ). During the postnatal development period of
0-10 days of age in the mouse testis, gonocytes, which are the precursors to SSCs,
give rise to both SSCs and differentiating spermatogonia (de Rooij 1998 ; Yoshida
et al. 2006 ). Thus, reduction of the germ cell population beginning at 8 days of age
and subsequent disruption of spermatogenesis in adulthood is likely a result of
impaired proliferation of both SSCs and differentiating spermatogonia. Evaluation
of spermatogenesis at 10 days of age and after puberty at 35 days of age in Mili −/−
mice also revealed reduced proliferation of spermatogonia (Unhavaithaya et al.
2009 ). These analyses indicate a general role of MILI in spermatogonial prolifera-
tion. By 98 days of age, seminiferous tubules display a Sertoli-cell-only phenotype
in Mili −/− mice, which is likely due to loss of all spermatogonia as a result of
impaired proliferation or a secondary effect of changes in Sertoli cell function
caused by degenerating germ cells. Specific examination of defects in SSC function
due to impaired MILI expression using functional transplantation or other measures
of SSC activity have not been reported. Thus, whether PIWI proteins, which are
essential for self-renewal of germline stem cells in D. melanogaster , have con-
served function in mammalian SSCs remains to be further defined.

7.3.3.2 NANOS2

Expression of the NANOS family of RNA binding proteins by germ cells is con-
served for several vertebrate and invertebrate species. In the mouse testis, expression
of NANOS2 is germ cell-specific beginning with PGCs after their migration to the
genital ridge and formation of seminiferous cords (Tsuda et al. 2003 ). Deletion of
NANOS2 causes PGC apoptosis and male mice contain only a few germ cells within
seminiferous tubules after birth (Tsuda et al. 2003 ); thus, the undifferentiated sper-
matogonial population never develops. In wild-type mice, NANOS2 expression is
restricted to the undifferentiated spermatogonial population including A s , A pr , and
some A al spermatogonia (Sada et al. 2009 ). Using a conditional deletion approach,
Sada et al. ( 2009 ) showed that disruption of NANOS2 expression in germ cells of
adult testes with active spermatogenesis results in rapid depletion of the undifferenti-
ated spermatogonial population in accordance with increased apoptosis. Furthermore,
overexpression of NANOS2 in the male germline resulted in accumulation of undif-
ferentiated spermatogonia and reduction in the number of the differentiating sper-
matogonia (Sada et al. 2009 ). Collectively, these findings imply an important role
for NANOS2 in maintenance of the undifferentiated spermatogonial population