[R01] Molecular and genetic control of astrocyte development
Ente: National Institute of Neurological Disorders and Stroke
Scadenza: 2031-04-30
Importo max: 439.069 EUR
Paese: US
Descrizione
Project Summary
Astrocytes are the most prevalent glial cell type in the human brain, and they play crucial roles in central
nervous system (CNS) development and function. Once mature, astrocytes exhibit a strikingly complex
morphology, ramifying numerous fine cellular processes that interact extensively with all CNS cell types. These
close interactions with other brain cells enable astrocytes to perform diverse and essential functions to
maintain CNS homeostasis, regulate nervous system assembly, and modulate neural circuits. Defects in the
development or maintenance of astrocyte morphological complexity have been implicated in many neurological
disorders, including Alzheimer’s disease, bipolar disorder, and schizophrenia. However, the mechanistic basis
of how astrocytes acquire their remarkably complex morphology remains poorly understood. The goal of our
lab is to understand the molecular, cellular, and genetic mechanisms underlying astrocyte morphological
growth and function. We use a synergistic combination of molecular-genetic tools and live-imaging techniques
in Drosophila and zebrafish model systems to deepen our fundamental understanding of astrocyte biology. We
recently uncovered that the phospholipid-binding G protein-coupled receptor (GPCR) Tre1/S1pr1 is required
for astrocyte morphological development in flies and fish. Loss of Drosophila Tre1 or its vertebrate counterpart
s1pr1 in zebrafish severely disrupts astrocyte morphological complexity, and changes in phospholipid (PL)
levels by manipulating the PL degrading enzyme Wunen/LPP3 in neurons can radically alter astrocyte fine
process outgrowth. Our data support a model in which neuron-astrocyte crosstalk regulates astrocyte
morphological establishment. In this proposal, we will use genetic, chemical, and in vivo imaging approaches in
zebrafish to define how the PL ligand is regulated in neurons versus astrocytes to direct astrocyte process
outgrowth and its role in neural circuit modulation (Aim 1). We employ the powerful genetics in Drosophila to
quickly dissect how GPCR signaling is regulated in astrocytes to control astrocyte development and function
(Aim 2), and we combine both model systems to determine how neuron-to-astrocyte signaling refines astrocyte
morphology (Aim 3). Our work will elucidate novel mechanisms by which astrocytes develop intimate
associations with neurons, how astrocyte morphology affects neural circuit activity and function, and lay the
foundation for our understanding of astrocyte function and dysfunction in human health and disease.
Istituzione: UNIV OF NORTH CAROLINA CHAPEL HILL
PI: Jiakun Chen
Progetto: 1R01NS143905-01A1
Settori: National Institute of Neurological Disorders and Stroke
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