[R35] The Developmental Transition of Neural Stem Cell Niches in the Human Brain
Ente: National Institute of Neurological Disorders and Stroke
Scadenza: 2033-07-31
Importo max: 1.178.168 EUR
Paese: US
Descrizione
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.
Istituzione: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
PI: Arturo Alvarez-Buylla
Progetto: 5R35NS143000-02
Settori: National Institute of Neurological Disorders and Stroke
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