MECHANISMS OF REGULATING ASTROGLIAL LINEAGE DEVELOPMENT

Project: Research project

Project Details

Description

DESCRIPTION: Using epidermal growth factor (EGF)-derived embryonic
subventricular zone (SVZ) multipotent neural progenitor cells, we have
identified a subclass of the transforming growth factor b (TGFb)
superfamily, the bone morphogenetic proteins (BMPs), that mediate the
selective, dose-dependent elaboration of astrocytes, with concurrent
suppression of neuronal and oligodendroglial lineage development.
Transcripts and proteins for the BMP ligands and BMP type I and II receptor
subunits are present in brain and SVZ progenitor cells at the appropriate
times to mediate these trophic actions. In concert with activation of the
LIFb receptor, BMPs and bFGF potentiate the early expression of radial glia,
with later enhancement (BMP) or inhibition (bFGF) of the astroglial
phenotype. These observations suggest that the BMPs represent a new class
of signaling molecules that may regulate astroglial lineage commitment and
may interact with distinct early signaling molecules. The general
hypothesis underlying this proposal is that the BMPs are instructive signals
that regulate astroglial lineage commitment, and that regulation of BMP
receptor subunits and/or BMP ligands determine the pattern of astrocyte
lineage elaboration during brain development: A. Clonal and single cell
analysis will be utilized to determine whether the BMP astroglial-promoting
effects constitute instructive cellular signals, whether different BMPs
suppress the neuronal and oligodendroglial lineages and whether progenitor
cell responsiveness to the BMPs in vitro correlates with changes in BMP
receptor expression. B. Isolated EGF-responsive progenitor cells and tissue
sections from sequential stages of gliogenesis will be examined to define
changes in the degree of BMP-progenitor cell responsiveness, the profile of
astroglial lineage species, and alterations in the spatiotemporal expression
of BMP receptors and ligands to establish in vitro-in vivo correlations. C.
The role of LIF and bFGF in modulating the BMP-mediated expression and
cellular responsiveness of radial glial populations will be studied to
determine whether these cellular changes reflect opposing effects on BMP
receptor expression. These studies will further our understanding of the
epigenetic signals and cellular mechanisms that regulate the development of
the astroglial lineage. Because many of the cellular processes present
during astroglial development may be recapitulated during pathological
states, these findings may also have important implications for our
understanding of glial-mediated responses in traumatic injury, demyelinating
disorders and mammalian central nervous system cellular transformation.
StatusFinished
Effective start/end date9/25/977/31/98

Funding

  • National Institute of Neurological Disorders and Stroke

ASJC

  • Cellular and Molecular Neuroscience
  • Developmental Neuroscience
  • Cell Biology
  • Pharmacology
  • Developmental Biology

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