Mouse models of Alazami syndrome reveal a developmental window of vulnerability in the hippocampal dentate gyrus to transcriptional dysregulation

Enhanced P-TEFb activity is thought to promote cell proliferation by increasing the transcriptional output of RNA polymerase II, and normally most cellular P-TEFb is inhibited by 7SK snRNP containing LARP7 and HEXIM1. Paradoxically, instead of causing overgrowth syndromes, loss-of-function mutations of LARP7 are linked to Alazami syndrome, a human neurodevelopmental disorder characterized by growth restriction and cognitive impairment. Here, we generate genetically engineered mouse models to investigate the etiology underlying Larp7 deficiency. Conditional knockout of either Larp7 or Hexim1 in the brain results in similar developmental defects as in human patients. Notably, the size and the function of the hippocampal dentate gyrus are markedly reduced. Multi-omics analyses and functional assays reveal that a heightened P-TEFb activity enhances the self-renewal transcriptional programs in Emx1+ neural progenitor cells to limit neurogenesis at the neonatal stage, resulting in dentate gyrus hypoplasia. These results demonstrate that dysregulated subtissular stem cell dynamics reconcile increased P-TEFb activity and cell proliferation with reduced organismal sizes. Because neonatal and adult dentate gyrus neurogenesis are highly alike, clinical-grade P-TEFb inhibitors, originally developed for treating cancer, may present a translational opportunity to ameliorate the adverse effects of several medical conditions on dentate gyrus size and function. Overall design: To identify differentially regulated pathways during neurosphere differentiation, RNA-seq profiling of wild-type and larp7 knockout neurosphere after 2 days differentiation. ATAC-seq profiling of wild-type and larp7 knockout neurosphere. CUT&Tag of RNA polymerase II, Pol II-Ser2 and Pol II-Ser5 in wild-type and larp7 knockout neurosphere. Single-cell RNA-seq was used to analyze cell compositions and functional states of the dentate gyrus, obtained from micro-dissected wild-type, Larp7f/f;Emx1-Cre, and Larp7f/f;nestin-Cre mutant mice at P7, respectively. To obtain enough materials, 3-4 dentate gyri from littermates were combined for each genotype.