The Harris
Lab Web Page
Research Interests:
Molecular Genetics of Sphingolipid Metabolism in
Drosophila
During the past several years my laboratory has become
focused on the analysis of sphingolipid metabolism
in flies. Sphingolipids are a complex and ubiquitous
class of membrane lipids found in most eukaryotic
cells. The bio-active sphingolipid polar metabolites:
ceramide, sphingosine and sphingosine-1-phosphate
have gained wide recognition for their involvement
in signaling pathways that regulate diverse cellular
activities such as proliferation, migration, apoptosis,
calcium mobilization, growth arrest and differentiation
- all of which are critical for the proper development
and function of an organism. We have identified eight
key enzymes in flies that regulate the synthesis of
these bioactive metabolites. Each of these enzymes
have highly homologous counterparts in humans. We
are characterizing mutations in genes that encode
these enzymes and have created transgenic flies that
mis-express them. By using this molecular genetic
approach to systematically perturb the accumulation
of the sphingolipid metabolites in vivo, we are gaining
novel insights into the physiological functions and
mechanisms of action of these enigmatic lipids.
The Roles of Sphingolipids in Drosophila
Development and Physiology
Most of our analyses of sphingolipid function have
been focused on various aspects of Drosophila
development. In collaboration with the laboratory
of Dr. Julie Saba at the Children's Hospital Oakland
Research Institute, we first discovered that mutations
in the gene encoding sphingosine-1-phosphate lyase,
a key degradative enzyme in the sphingolipid metabolic
pathway causes a profound accumulation of both phosphorylated
and unphosphorylated sphingolipid metabolites. The
dramatic rise in accumulated sphingolipids occurs
early in development and leads to: 1) abnormalities
in the numbers, morphology, function and integrity
of skeletal muscles; 2) reproductive defects affecting
both the ovaries and testes leading to diminished
fecundity; 3) disruption of fatty acid metabolism;
and, 4) markedly reduced viability and lifespan. Since
that initial study we have analyzed mutations affecting
sphingosine kinase, serine palmitoyltransferase and
sphingosine desaturase. Each mutation causes unique
sets of phenotypes that affect muscle, reproductive
and nervous system function and alter global lipid
homeostasis. The central hypothesis of our work is
that tight regulation of sphingolipid metabolism is
critical for normal development and the subsequent
function of adult tissue. We are currently analyzing
developmental defects in muscle, gonads, adipose tissue
and the nervous system associated with mutations of
in each of the key metabolic enzymes that have been
identified. For these studies, we use a series of
genetic, behavioral, physiological, biochemical, molecular
and morphometric-based analytical approaches. It is
anticipated that this work will form a firm and novel
foundation for understanding the roles that specific
sphingolipid molecules play in the development and
physiology of complex animals.
Molecular Genetic Analysis of Obesity
Obesity is a multi-factorial metabolic disorder that
results in excessive accumulation of body fat and
is associated with related pathologies including diabetes,
coronary heart disease and cancer. A variety of genetic
lesions that tip the balance between food intake and
energy expenditure can lead to phenotypes that lie
along a broad spectrum ranging between obesity and
starvation. In our work using Drosophila
as a model organism for the molecular genetic dissection
of sphingolipid metabolism we have discovered that
disruption of the sphingolipid metabolic pathway can
lead to the development of obesity as assessed by
increased body weight, elevated triglycerides and
excess deposition of fat. To our knowledge, this is
the first time that sphingolipid metabolism has been
linked to obesity and given the global derangement
of lipids that occurs in sphingolipid metabolic mutant
flies, it seems likely that the proposed work will
shed light on the molecular mechanisms that regulate
the flow of lipids through the various compartments
and metabolic pathways within an organism.
Recent Related Publications:
Deron R. Herr and Greg L. Harris (2004). Close head-to-head
juxtaposition of genes favors their coordinate regulation
in Drosophila melanogaster. FEBS Letters,
572:147-153.
Deron R. Herr, Henrik Fyrst, Michael Creason, Van
Phan, Julie D. Saba & Greg L. Harris (2004). Characterization
of the Drosophila sphingosine kinases and
requirement for SK2 in normal reproductive function.
J. Biol Chem. 279(13):12685-12694.
Henrik Fyrst, Deron R. Herr, Greg L. Harris and Julie
D. Saba (2004). Characterization of Endogenous C14
and C16 Sphingoid Bases in
Drosophila. J. Lipid Res. 45-54-62.
Deron R. Herr, Henrik Fyrst, Van Phan, Karie Heinecke,
Rana Georges, Greg L. Harris & Julie D. Saba.
(2003). Sply regulation of sphingolipid signaling
molecules is essential for Drosophila development.
Development. 130(11):2443-53.
Ph.D.
students: Van Phan and Steve Attle
M.S. students: Greg Brulte, Khanichi
Tape, Stan Walls and Bryan Bartlett
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