Role of Phosphoinositides
in Developmental Neurobiology
Many diseases are linked to dysregulation of second messenger signaling
cascades. One important second messenger system is the phosphoinositide (PI) system, in
which inositol lipids function as second messengers and cofactors for many cellular
activities stimulated by growth and trophic factors, hormones, cytokines, and
neurotransmitters. My research focuses on investigating the intracellular targets for
several of the PI second messengers in the nervous system. We are particularly interested
in the function of PtdInsP3 in neurons and glia, since we have demonstrated that this
lipid is required for cells to extend processes, termed neurites, in response to trophic
factors and extracellular matrix. Neurites eventually form mature axons and dendrites,
which contact each other at synapses, and allow for information transfer between neurons.
Using biochemical and molecular techniques, we have isolated and cloned several novel
phosphoinositide receptors from brain. One of these receptors is involved in regulating
vesicle trafficking and the actin cytoskeleton, two activities which are involved in
neurite outgrowth and new synapse formation. Studies are underway to determine the role of
these receptors in neuronal development and synapse formation, and the molecular
mechanisms which regulate receptor expression, targeting to intracellular compartments,
and modulation of activity. Several potential homologues of these receptors are present in
the genetically tractable organism, Saccharomyces cerevisiae, which allows us to use yeast
genetics to complement the biochemical and molecular approaches in dissecting the function
of these brain phosphoinositide receptors.
