The P-body protein 4E-T represses translation to regulate the balance between cell genesis and establishment of the postnatal NSC pool

Highlights

• Postnatal neural stem cells express neurogenic mRNAs, but not their proteins

• The translational regulator 4E-T sequesters and represses these mRNAs in P-bodies

• 4E-T loss derepresses neurogenic mRNAs, resulting in aberrant neurogenesis

• 4E-T ensures the stem cell pool is not depleted during a time of rapid cell genesis

Summary

Here, we ask how developing precursors maintain the balance between cell genesis for tissue growth and establishment of adult stem cell pools, focusing on postnatal forebrain neural precursor cells (NPCs). We show that these NPCs are transcriptionally primed to differentiate and that the primed mRNAs are associated with the translational repressor 4E-T. 4E-T also broadly associates with other NPC mRNAs encoding transcriptional regulators, and these are preferentially depleted from ribosomes, consistent with repression. By contrast, a second translational regulator, Cpeb4, associates with diverse target mRNAs that are largely ribosome associated. The 4E-T-dependent mRNA association is functionally important because 4E-T knockdown or conditional knockout derepresses proneurogenic mRNA translation and perturbs maintenance versus differentiation of early postnatal NPCs in culture and in vivo. Thus, early postnatal NPCs are primed to differentiate, and 4E-T regulates the balance between cell genesis and stem cell expansion by sequestering and repressing mRNAs encoding transcriptional regulators.