The Developmental Transition of Neural Stem Cell Niches in the Human Brain

Project Summary Our earlier work identified the neural stem cells (NSC) and intermediate progenitors that generate new neurons and glial cells in the adult mouse brain. These NSCs are regionally specified to produce unique sets of inhibitory interneurons that migrate along the rostral migratory stream (RMS) to the olfactory bulb. Unlike rodents, the adult human brain does not contain an RMS, but this and other migratory streams are present in infants. In young children, we recently found two major streams of migrating young neurons (the ARC and the EC stream) that supply inhibitory cortical interneurons (cIN) to the frontal and entorhinal cortices respectively. The neuronal progenitor cells that generate these postnatally recruited young neurons have not been identified. Our overall goal for the next 8 years is to investigate how NSC niches transition from embryonic to postnatal stages in the human forebrain. We aim to characterize the different NSCs and progenitor populations involved in the production of large numbers of cINs required for the greatly expanded human neocortex. We plan to focus on the ventral forebrain germinal regions, in particular, on the caudal ganglionic eminence (CGE), which is the source of half of all cINs in humans, including the majority of cells observed in the ARC and the EC stream. CGE-derived cINs are considered key to higher cognitive function, and dysregulation of their numbers has been linked to neurological disorders and tumor formation. We hypothesize that the human CGE has increased its output of cINs by (1) increasing the proliferation of intermediate progenitors at multiple stages in the cIN lineage, and (2) extending the period of neurogenesis into postnatal life. We propose to use multi-omics, spatial transcriptomics, and electron and light microscopy to investigate the cellular composition and organization of the human CGE. We aim to identify the different CGE progenitor populations and how this germinal niche is organized. Preliminary data suggests that epidermal growth factor receptor (EGFR) could be key to CGE intermediate progenitor amplification. Using CGE organoids and genetic approaches in mice, we will investigate the role of EGFR signaling in CGE neurogenesis and gliogenesis. We will then study what progenitor cells persist postnatally in the CGE and other ganglionic eminences and how their niches change from prenatal to postnatal stages. Finally, we propose to resolve the controversy of whether NSCs in the postnatal brain produce both neurons and glial cells in vivo. The proposed work will elucidate how cIN production is amplified to satisfy the needs for a greatly expanded human neocortex. This basic new knowledge of human brain development could lead to novel approaches for the treatment of neurological disorders and the identification of progenitor cells implicated in tumor formation.