Proper balance of differentiation vs. proliferation in the germline stem/progenitor cell pool is crucial for gamete production and reproductive fitness. We are using C. elegans larval germline development as a model to study the developmental and physiological control of this balance.
We showed that RSKS-1, the C. elegans ortholog of the Target of Rapamycin (TOR) substrate
p70-S6-Kinase (S6K), promotes accumulation of progenitor cells germline-autonomously. In this role,
rsks-1 both promotes larval germline cell cycle and inhibits differentiation, together with GLP-1/Notch. Loss (lf) of
rsks-1 both enhances the progenitor maintenance defect in reduced (rf)
glp-1 mutants and suppresses tumor formation in elevated (gf)
glp-1 (Korta et al. 2012). More recently, we showed that the cell fate role of
rsks-1 is germline-automomous: germline
rsks-1(+) rescues progenitor loss in
glp-1(rf)
rsks-1(lf).
TOR also positively regulates translation initiation factor-4E (eIF4E). We found that
ife-1 (eIF4E ortholog in the germline) is required for optimal expansion of the larval progenitor pool.
rsks-1(lf)
ife-1(lf) produce fewer progenitors than either single mutant (Korta et al., 2012). To assess a possible cell fate role for
ife-1, we examined
glp-1(rf)
ife-1(lf) double mutants. Unlike
glp-1(rf)
rsks-1(lf), the
ife-1 double retains a progenitor pool, albeit with fewer cells than either single mutant. Similar results are seen in
glp-1(rf);
let-363/TOR (RNAi), or upon food reduction, suggesting a unique role for S6K in progenitor maintenance.
Reducing
cye-1/Cyclin-E by RNAi causes a loss of the progenitor pool in
glp-1(rf) (Fox et al. 2011), similar to
rsks-1(lf). We are investigating the interactions between
rsks-1,
glp-1 and
cye-1. Loss of RSKS-1 does not affect the level or pattern of CYE-1 protein expression, arguing against a general translational control mechanism. Our data suggest a model whereby RSKS-1 acts together with CYE-1, but in parallel with GLP-1, to inhibit differentiation.