DYNAMIN AND NEURONAL MORPHOGENESIS

  • Urrutia, Raul Alfredo (PI)

Project: Research project

Project Details

Description

Proper functioning of the mammalian nervous system depends on a specific
wiring pattern determined by a developmental program. This program
directs how neurons divide at early stages, migrate to their final
destination, outgrow cell processes and, finally, establish synapses with
other neurons or a distinct target cell. A significant number of human
diseases occur as a result of an aberrant completion of this
developmental program. Many of these diseases, including Down's
Syndrome, several forms of congenital mental retardation,
phenylketonuria, malnutrition and schizophrenia are characterized by
neurons with an alteration in the normal structure and number of
neurites. Microtubules and microtubule-associated proteins and enzymes
are known to play a crucial role in the development of normal wiring
patterns in the nervous system by taking part in the extension of
neuronal processes. Our laboratory is focused on the role of a specific
microtubule-associated enzyme, dynamin, in the extension of neuronal
processes. Dynamin is a microtubule-activated GTPase that binds and
cross-links microtubules in vitro in a nucleotide-dependent manner and
therefore has been proposed to act as a microtubule-based motor in vivo.
We have made important preliminary observations which indicate that 1)
dynamin is essential for neurite formation and 2) dynamin is localized
at the neuronal growth cone. In addition, we have cloned a novel dynamin
gene encoding a second isoform expressed in rat brain. From these
studies, we hypothesize that dynamin contributes to the formation of
neurites during development by: a) maintaining the normal structure of
neuronal processes through cross-linking and positioning microtubules in
the neurite and b) participating in the endocytic recycling of proteins
which are important for neurite outgrowth. We have designed experiments
to correlate the level of dynamin with the formation of neurites in both
hippocampal neurons and PC12 cells developing in vitro. Furthermore,
additional studies are aimed to alter the expression of dynamin using
antisense technology and determine whether a reduced level of this
protein impairs neurite outgrowth. We will use state-of-the-art video
and electron microscopy in combination with molecular biological
techniques to determine the integrity of the microtubule network and
endocytic vesicular transport pathway in the dynamin minus neurons. To
our knowledge, this is the first study which has provided insight into
the in vitro role of dynamin in neuronal development. We are optimistic
that a detailed characterization of the mechanisms involved in neurite
formation will help us better understand many mental diseases.
StatusFinished
Effective start/end date5/1/944/30/99

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

ASJC

  • Medicine(all)
  • Neuroscience(all)

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