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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE300207 | GEO | 2026/02/14

REPOSITORIES: GEO

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Project description:Many genotoxic agents that block replication fork progression to cause DNA replication stress also block transcription, which results in transcription stress. The 7SK-small nuclear ribonucleoprotein (7SK-snRNP) regulates and promotes RNA polymerase II activity in response to transcription blocks. Individual 7SK-snRNP components HEXIM1, LARP7 and MEPCE are also reported to either facilitate or inhibit processes relevant to replication stress: conflicts between transcription and replication and homologous recombination (HR) at double-strand breaks (DSBs). Here, we investigate potential roles of 7SK-snRNP components in the response to replication stress-inducing agents such as camptothecin and hydroxyurea. We report that HEXIM1 and LARP7 promote replication fork slowing in response to agents that cause both replication- and transcription stress, in a manner consistent with their canonical 7SK-snRNP functions. Our data suggest that this role in fork slowing is mainly through facilitating RAD51-mediated replication fork reversal rather than transcription-replication conflicts. HEXIM1 and LARP7 promote RAD51 recruitment to replication-associated DSBs or post-replicative gaps under conditions of transcription stress such as induced by camptothecin or BET inhibitors, while to a lesser extent supporting HR at direct DSBs and not at all in absence of transcription stress. Our data support that LARP7 roles during replication stress are independent of its reported interaction with BRCA1 and both LARP7 and HEXIM1 promote survival of replication stress-inducing agents, especially camptothecin. 7SK-snRNP components are not recruited to stressed replication forks and RNA polymerase II inhibition phenocopies loss of these proteins. Taken together, our data support a model where 7SK-snRNP modulation of RNA polymerase II activity helps facilitate RAD51 function under transcription stress conditions, thereby linking the cell responses to transcription- and replication stress.

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

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