REGULATION OF NEURONAL MITOSIS

  • Dreyfus, Cheryl (PI)
  • Schleifer, Leonard (PI)
  • Hempstead, Barbara (PI)
  • Adler, Joshua (PI)
  • Ablack, Ira (PI)
  • Chao, Moses Victor (PI)
  • Zheng, James (PI)
  • Dicicco-Bloom, Emanuel (PI)
  • Dreyfus, Cheryl (PI)
  • Dicicco-Bloom, Emanuel (PI)
  • Dreyfus, Cheryl (PI)
  • Varia, Smita (PI)
  • Black, Ira (PI)
  • Black, Ira (PI)
  • Black, Ira (PI)
  • Chao, Moses (PI)
  • Wu, Kuo (PI)
  • Black, Ira (PI)
  • Ablack, Ira (PI)
  • Chao, Moses (PI)
  • Schleifer, Leonard (PI)
  • Adler, Joshua (PI)
  • Chao, Moses (PI)
  • Wu, Kuo (PI)
  • Black, Ira (PI)
  • Wu, Kuo (PI)
  • PLUMMER, MARK (PI)
  • ZHOU, RENPING (PI)
  • Wu, Kuo (PI)

Project Details

Description

While the generation of neurons in the peripheral (PNS) and central
nervous systems (CNS) is highly reproducible spatially and temporally,
little is known of regulatory mechanisms. During the previous award we
developed a model PNS sympathetic cell culture system of dividing
precursors (neuroblasts) and found that insulin growth factors (IGF's),
EGF, and transsynaptic signals were highly specific mitogens. We now
hypothesize that a). population-specific epigenetic factors regulate CNS
ontogeny including proliferation, differentiation and survival, and b).
environmental signals regulate ontogenetic processes independently. Our
recent development of a brain neuroblast system, composed of cerebellar
granule neurons and precursors, now allows definition of mitogenic and
trophic factors, second messengers and interacting cellular programs in
CNS neurogenesis.

Our specific aims are to define epigenetic signals regulating brain
precursors and to characterize relationships of division to neuronal
differentiation in PNS and CNS populations. Second, extending our
discovery that VIP is a developmentally regulated mitogen and trophic
factor, we plan to characterize peptide production and intracellular
transduction mechanisms. Third, we will define the role of Id, a member
of the helix-loop-helix transcription factor family, in mediating
neuroblast response to epigenetic signals.

Our strategy employs pure populations of PNS and CNS neuroblasts in
serum-free culture. We examine trophic and mitogenic effects by
assaying cell number and [3H]thymidine incorporation, using
autoradiography and scintillation spectroscopy. Video-enhanced DIC
time-lapse image analysis will be employed to define relationships of
mitosis to differentiation and epigenetic regulation. We will define
mechanisms of VIP production by assaying peptide and mRNA levels in vivo
and in vitro. Second messenger systems mediating VIP effects will be
assessed by characterizing peptide-induced phosphorylation of exogenous
and endogenous proteins. Finally, the expression and epigenetic
regulation of Id will be characterized by in situ hybridization,
Northern analysis, and immunocytochemistry in vivo and in culture.

By characterizing population-specific epigenetic signals and intrinsic
molecular mechanisms regulating neuroblast mitosis, we hope to identify
unrecognized loci where disease processes intervene to derange
neurogenesis. In turn, we may gain insight into mechanisms underlying
congenital diseases such as neuronal systems degeneration, and neural
tube dysgenesis and potentially design novel approaches to brain repair.
StatusFinished
Effective start/end date1/1/016/30/15

Funding

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development: $1,455,209.00
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development: $1,464,848.00
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development: $1,376,743.00
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development: $1,416,325.00
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development: $1,436,589.00
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development: $1,455,015.00
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development: $1,422,280.00

ASJC

  • Medicine(all)
  • Clinical Neurology
  • Neurology
  • Genetics
  • Accounting
  • Molecular Biology
  • Biochemistry
  • Physiology
  • Neuroscience(all)
  • Cell Biology
  • Histology
  • Pharmaceutical Science

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