Enhanced P-TEFb activity compromises dentate gyrus neurogenesis in mice

Enhanced P-TEFb activity is thought to promote cell proliferation by increasing the transcriptional output of RNA polymerase II. The 7SK snRNP complex, which contains LARP7 and HEXIM1, sequesters and inhibits most cellular P-TEFb to prevent premature transcription elongation. Paradoxically, instead of exerting overgrowth effects, biallelic inactivation of LARP7 is linked to Alazami syndrome, a human neurodevelopmental disorder characterized by growth restriction and cognitive impairment. Here, we report that conditional ablation of either Larp7 or Hexim1 in the murine brain reduces the size and impairs the function of the hippocampal dentate gyrus during the neonatal period. Functional analyses reveal that increased P-TEFb activity enhances self-renewal transcriptional programs in transit-amplifying neuronal progenitor cells to limit neurogenesis in developing dentate gyri. These results demonstrate that dysregulated subtissular stem cell dynamics can reconcile increased P-TEFb activity with reduced organ growth, and suggest a translational opportunity for repurposing P-TEFb inhibitors to treat medical conditions affecting dentate gyrus size and function.