Programmed cell death: Our aim is to understand the molecular events underlying the
process of programmed cell death (PCD), a characteristic form of cell death that occurs during
the development of all multicellular animals. PCD is important for proper development and is
misregulated in several disease states in humans, including cancer, neurodegenerative diseases,
and stroke. We are interested in understanding how developmental cell fate signals regulate
PCD, a problem currently not well understood. Our studies employ the nematode C. elegans
where we and others have described an evolutionarily conserved core molecular program
functioning to regulate PCD. We are performing genetic screens to identify genes that regulate
PCD and that link cell fate decisions to regulation of cell survival. We have identified
several potential regulators. One regulator we described, the gene ced-13, promotes
PCD primarily in response to radiation-induced DNA damage. The CED-13 protein contains a BH3
(Bcl-2 Homology 3) domain that binds and presumably inactivates the C. elegans
Bcl-2-related protein CED-9, a death-protecting protein. Interestingly, CED-13 seems to be
specifically induced by the C. elegans p53-related protein CEP-1. These results,
together with the remarkable conservation of PCD components from nematodes to humans, suggest
that we have identified a key pathway connecting the p53 tumor suppressor gene to the core PCD
machinery. In addition to characterizing potential regulators obtained from our genetic screens,
studies in the lab focus on:
- Investigating the role of transcriptional activation of the ced-3 caspase gene in regulating PCD.
- Investigating the roles and mechanisms of action of BH3-domain proteins in regulating PCD.
- Identifying and characterizing additional genes required for the global execution of PCD.
Glial cell development and function: Glia make up over 90% of the cells populating the
human brain, and glia-derived tumors are the most common and most lethal human brain tumors.
Surprisingly, compared to their neuronal counterparts, little is known about glial cell
development, function, or morphogenesis. Growing evidence suggests that glia play active
roles in regulating synaptic transmission and neuronal current propagation, and are likely to
play key roles in many, if not all, aspects of nervous system function.
C. elegans contains 24 neuron-associated cells termed sheath cells that bear striking
similarities to vertebrate glia. Reminiscent of astrocytes, they possess a large cell body
with multiple small projections and a long main projection that enwraps the dendritic processes
of sensory neurons. Recent availability of C. elegans glial reporter genes, the
sequencing of the entire C. elegans genome, and the facility with which genetic studies can
be undertaken in this organism make it an excellent system to study basic aspects of glial cell
biology. C. elegans sensory structures are composed of three cell types: sensory neurons
responsive to odor, osmolarity, mechanical stimuli and heat; sheath cells that associate with
the neurons and envelope the distal ends of their dendritic processes; and socket cells
involved, in part, in generating a pore through which chemical signals can be sensed by the
ensheathed neurons. Two bilaterally symmetric sensory structures, the amphids and phasmids,
seem to be important for most chemosensation in C. elegans. Because the neurons of the
amphids and phasmids have been well characterized, we have chosen to study the functions of
their accompanying glia as a model for understanding glial cell development and function. We
are interested in two aspects of support cell biology: how ensheathing cells modulate neuronal
function, and how they acquire their unique morphologies. We have begun to address these
questions using a combination of laser ablation, time-lapse microscopy, genomic and genetic
approaches.
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