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Full Abstracts – PLENARY SESSION I
115
Regulation of energy metabolism in
Drosophila
.
Carl S. Thummel, William Barry, Daniel Bricker, Janelle Evans, Michael Horner, Geanette Lam, Jyoti
Misra, Daniel Seay, Matthew Sieber, Rebecca Somer, Jason Tennessen, Wendou Yu. Dept of Human Genetics, Univ Utah School of Med., Salt Lake City,
UT.
Energy metabolism is central to all aspects of animal life. Dietary nutrients are either set aside as stored reserves or burned to provide the energy needed
for daily survival. Conversely, misregulation of metabolism is central to human disease - in particular the alarming rise in the incidence of diabetes and
obesity. We are using
Drosophila
as a model system to define the molecular mechanisms of metabolic control and to better understand the causes of
metabolic disorders. There are three projects currently underway in the lab. The first is focused on how nuclear receptors sense small metabolites and
regulate the transcription of genes that play central roles in specific metabolic pathways. These studies currently address how dHNF4 maintains energy
homeostasis under conditions of nutrient depletion, the role of dERR in regulating developmental growth, and the control of lipid metabolism by DHR96.
The second project is a collaborative effort aimed at defining the functions of uncharacterized mitochondrial proteins that are conserved through evolution
from yeast to humans. Current efforts are focused on two families of mitochondrial proteins, one of which appears to act as the long-sought pyruvate
transporter that links cytoplasmic glycolysis with mitochondrial energy production, while the second protein family appears to regulate mitochondrial fatty
acid oxidation. The third project is studying how temporary changes in parental diet can affect the metabolic state of their offspring. Hundreds of studies in
rodents and humans have linked parental nutrition to metabolic dysfunction in subsequent generations. Although this transgenerational inheritance is thought
to be epigenetically programmed, the published work in this area is only correlative. We have reproduced these effects in
Drosophila
and aim to define the
molecular mechanisms involved.
Behavioral and anatomical analysis of the neural circuits that drive fly grooming.
Julie H. Simpson, Stefanie Hampel, Primoz Ravbar, Andrew M.
Seeds. HHMI, Janelia Farm Res Campus, Ashburn, VA.
We use Drosophila grooming behavior as a model to understand the neural circuit architecture that allows the brain to construct complex behavioral
sequences from simpler reflexes and subroutines. Flies remove debris using an ordered progression of leg sweeps and rubs. The local subroutines needed to
remove dust resemble the scratch reflex and can be discretely triggered or blocked. When the whole body is covered with dust, the fly grooms its anterior
before proceeding to clean its posterior. Our detailed analysis of the way wild-type flies groom suggested both the modular organization of subroutines and
the ordered progression between them. We conducted screens in which we activated or inhibited neural activity in different sets of neurons and determined
the effect on spontaneous grooming and dust removal. The range of phenotypes we observed supports our hierarchical model of grooming, and the GAL4
lines targeting key neurons provide anatomical entry points to the circuitry that drives the behavior. We have identified sensory, motor, and interneurons that
affect grooming. We are using a range of genetic tools to identify the minimal groups of neurons and circuits required for both the execution of behavioral
subroutines and the coordinated progression of the grooming sequence.
News from the Niche.
Stephen DiNardo
1,2
, Tishina Okegbe
1,2
, Lindsey Wingert
1,2
, Qi Zheng
1,2
, Judith Leatherman
3
. 1) Dept Cell & Developmental Biol,
Perelman Sch Medicine; 2) Institute for Regenerative Medicine, Univ. Pennsylvania, Philadelphia, PA; 3) College of Natural and Health Sciences,
University of Northern Colorado.
Niches regulate the behavior of many tissue-specific stem cells. However, in no case do we fully understand how a niche is specified and assembled in a
tissue, and then how it executes control over stem cells. In the Drosophila testis, a small group of cells (hub cells) acts as part of the niche, leading to the
activation of renewal pathways in adjacent cells. In this manner, nearby somatic cells adopt cyst stem cell fate (CySC), while nearby germline cells,
intermingled with these CySCs, adopt germline stem cell fate (GSC). Work from us and others recently clarified how this niche operates, bringing together
disparate observations into a cohesive framework. In particular we found that the CySCs are doubly intriguing. Aside from acting as stem cells, producing
daughter cells that form an instructive epithelial ensheathment for differentiating germ cells, our work now shows that CySCs are also part of the niche: they
act together with hub cells to renew the GSCs. We further showed that the zinc finger homeodomain protein Zfh1 governs both of these CySC properties,
and is expressed highly in CySCs and dramatically downregulated both in the epithelial hub, and in their differentiating epithelial cyst progeny Our new
focus on CySCs also led us to discover that hub cells and CySCs derive from a common pool of somatic gonadal precursor cells (SGPs) during
gonadogenesis. Their common derivation provides some understanding for why hub cells and CySCs can each act as niche cells for the germline. But, more
importantly, their lineal relationship drove us to investigate how somatic cells within the common SGP pool choose between hub fate and CySC fate, and
how the hub forms during gonadogenesis. Our work, along with van Doren’s, Tanentzapf’s, Kobayashi’s and Wawersik’s, generates a model for the steps
that occur before the hub can act as a niche. This presentation will summarize that progress and the outstanding questions that yet require resolution.
Lipoproteins in human and Drosophila Hedgehog signaling.
Suzanne Eaton, Wilhelm Palm, Marta Swierczynska, Veena Kumari. The Max Planck
Institute of Molecular Cell Biology and Genetics, Germany.
Hedgehog (Hh) family proteins play crucial roles in development and tissue homeostasis. Although they are covalently linked to both sterol and palmitate,
they are secreted and can spread over long distances to receiving cells. In Drosophila, lipoproteins act as vehicles for the spread of Hh, but also repress the
pathway in a ligand-independent manner. Here, we establish similar functions for lipoproteins in human Shh signaling. We further show that both human
and Drosophila cells can secrete Shh/Hh in two distinct forms - as sterol-modified Hh proteins associated with lipoproteins, or, when lipoproteins are not
available, as non-sterol-modified monomers or dimers (Shh-N*/Hh-N*). The association of Shh/Hh with lipoproteins alleviates their repressive effect on the
pathway. Hh-N* and Shh-N* exert complementary effect to lipoprotein-associated forms, suggesting these distinct forms of Hh affect the pathway in
different ways.