Chromatin regulatorKdm6bis required for the establishment and maintenance of neural stem cells in mouse hippocampus

Abstract

ABSTRACTNeural stem cells (NSCs) in the mouse hippocampal dentate gyrus (DG) – a structure important to learning and memory – generate new neurons postnatally and throughout adult life. However, the regulators that enable this lifelong neurogenesis remain incompletely understood. Here we show that the chromatin regulator KDM6B is required for both the establishment and maintenance of NSCs in the mouse DG. Conditional deletion ofKdm6bin embryonic DG precursors results in an adult hippocampus that is essentially devoid of NSCs, and hippocampal-dependent behaviors are defective.Kdm6b-deletion causes precocious neuronal differentiation, and the NSC population fails to become established in the postnatal DG. Using single cell RNA sequencing (scRNA-seq), we observed thatKdm6b-deletion disrupts the transcriptomic signature of NSC maintenance. Furthermore, deletingKdm6bin adult DG NSCs induces early neuronal differentiation, and the NSC population is not properly maintained. These data illustrate the critical role thatKdm6bplays in adult DG neurogenesis, which may help understand how mutations in this chromatin regulator result in cognitive disorders in human patients.