Fig. 10

Model showing how cross-regulation of Dcp1a and Fmrp alters the balance of mRNA turnover and translation. The balance of Dcp1a and Fmrp are hypothesized to control the turnover and translation of different sets of transcripts in distinct cellular states (middle row). When wild-type proliferating myoblasts (MB, center) enter quiescence (G0, left), protein synthesis is repression and stalled polysomes are detected, paralleled by enrichment of the translational repressor Fmrp into prominent puncta, whereas Dcp1a puncta diminish. In contrast, differentiation (MT, right) is associated with a reduction of both Fmrp and Dcp1a puncta, suggesting a new set point for the balance of these regulators. Perturbing expression of Dcp1a (upper row) or Fmrp (lower row) has reciprocal effects on mRNP granules, and opposing phenotypic consequences. Depletion of Dcp1a leads to increased Fmrp accumulation and assembly, whereas depletion of Fmrp leads to increased Dcp1a accumulation and assembly. Dcp1a knockdown (upper row) may increase levels of proteins that enhance cell proliferation directly (via reduced mRNA turnover), and indirectly act via increasing Fmrp to reduce translation of negative cell cycle regulators. Such hyper-proliferative Dcp1a knockdown cells are resistant to induction of quiescence. Conversely, Fmrp knockdown (lower row) may increase levels of proteins that repress the cell cycle directly (via de-repressed translation), and indirectly decrease levels of proteins that positively regulate the cell cycle (via increased Dcp1a and increased turnover of transcripts). Thus, Fmrp knockdown cells show reduced cell proliferation and Dcp1a knockdown cells show increased proliferation. The observations that normal induction of quiescence leads to increased Fmrp accumulation, whereas forced suppression of Fmrp also decreases proliferation, suggest that a threshold of Fmrp accumulation/assembly is required to balance between proliferation and quiescence. The observation that depletion of either Dcp1a or Fmrp leads to compromised differentiation may be explained by altered net translation of different sets of pro- and anti-myogenic target transcripts