UCSF

The mammalian brain contains complex regional structures that emerge from heterogeneous populations of neural stem cells (NSCs) during development. Through the process of embryogenesis, NSCs gain positional identities as a result of morphogen signaling, organizing them into distinct lineage-restricted domains. These domains persist from the embryo into the ventricular-subventricular zone (V-SVZ), a postnatal stem cell niche lining the lateral walls of the lateral ventricles. Yet, how NSCs maintain these identities as the brain expands is not known. Here I show that ventral NSCs can maintain region-specific gene expression independently of morphogen Sonic hedgehog (Shh), which initially confers ventral identity. Instead, ventral identity is preserved by chromatin modifier Mixed lineage leukemia 1 (Mll1), which functions as part of an epigenetic memory system. Interfering with MLL1 activity causes a persistent loss of ventral identity, leading NSCs to produce neurons resembling those of dorsal origin. To gain more insight into the differences between NSCs in the V-SVZ, we conducted single-cell and single-nucleus RNA sequencing of the niche. We find that positional identity is a strong driver of both NSC and neuroblast heterogeneity in the V-SVZ, allowing us to identify novel markers of the dorsal and ventral NSC lineages. A subset of region-specific genes is maintained from NSCs through the intermediate progenitor stage and into neuroblasts, giving insight into the extent and timing of NSC lineage commitment. Together, these findings help explain how NSCs in the developing and postnatal brain remember the positional information necessary to produce the brain’s characteristic anatomical complexity.