The human brain receives, processes, stores and transmits
complex information with great fidelity. The neuronal network
that underlies these functions is comprised of an estimated
1011 neurons linked by over 1014
synaptic connections, an extraordinary example of biological
complexity and specificity. During development the cells
of the brain become specialized for particular functions,
are grouped into anatomically discrete structures within
the brain and are connected to one another in a highly specific
fashion. What are the molecular mechanisms that control
the development of such neural circuits? How do these circuits
control behavior?
My lab examines these questions in the fruit fly Drosophila
melanogaster. The powerful molecular genetic tools available
in Drosophila combined with the relative anatomical
simplicity of the fruit fly nervous system make Drosophila
a favorable system for discovering the molecular mechanisms
that control nervous system development and behavior.
Research Summary
We are interested in understanding the origins of behavior
at the molecular level by studying both neuronal development
and behavior. Our work on neuronal development focuses on
how neurons acquire specific shapes and how they form connections
with their targets. Our work on the molecular mechanisms
of behavior focuses on how animals sense and respond to
gradations of a ubiquitous environmental stimulus, temperature.
Neuronal Morphogensis and Connectivity:
Neurons are highly polarized cells that use their asymmetric
organization to carry out the essential functions receiving
and transmitting information in the nervous system. Our
work on neuronal morphogenesis investigates how the spatial
relationships of a neuron's distinct parts (nucleus, axon,
etc…) are established and maintained using the Drosophila
photoreceptor neurons as a molecular genetic model system.
We have recently found that the minus-end directed microtubule
motor Dynein and the Dynein-regulator Dynactin act antagonistically
to the plus-end directed microtubule motor Kinesin to maintain
the position of the nucleus within the differentiating photoreceptor
(Whited et al., 2004). How do these microtubule motors control
nuclear position within the neuron? How is nuclear position
coupled to the overall polarity of the neuron? We are addressing
these basic questions in the cell biology of neurons through
a combination of molecular, genetic and imaging studies
in the Drosophila eye.
Neuronal morphogenesis is also involved in the construction
of circuits necessary for behavior, and we are studying
the maintenance and plasticity of connections between neurons
and their targets. We have identified two evolutionarily
conserved signaling pathways that have important influences
on these processes. One pathway involves the non-receptor
protein tyrosine phosphatase, PTPMEG (Whited et al.,), while
the second involves the small GTPase Rab11 and its novel
antagonist Bchs (Khodosh et al., 2006). In both cases, we
are using molecular genetics in the fly to learn more about
how these conserved signaling molecules act to modulate
axonal and synaptic morphology.
Thermosensory Behavior:
A long-term goal of neuroscience is to understand how neural
circuits established during development regulate behavior.
My lab uses thermotaxis, directed migration guided by differences
in temperature, to study this fundamental question. Animals
avoid temperatures that are harmful and gravitate toward
temperatures that are hospitable and/or associated with
food. How are gradations in thermal energy converted into
patterns of electrical activity that guide behavior? The
molecular and genetic tools available in Drosophila melanogaster
facilitate addressing three basic questions: What are the
critical molecules involved in detection of temperature?
What are the neuronal circuits that mediate temperature-dependent
behavior? How do these circuits combine to modulate behavioral
responses? Answering these questions will help illuminate
both how temperature can be sensed and, more broadly, the
molecular and cellular basis of animal behavior.
Using behavioral assays and rapid RNAi-based gene survey
approaches devised in our lab, we recently identified the
first regulator of Drosophila thermotaxis, dTRPA1 (Rosenzweig
et al., 2005). Larvae lacking dTRPA1 fail to turn back when
they encounter regions that are too warm, a behavioral defect
with dire consequences. dTRPA1 behaves as a temperature-activated
cation channel when expressed in heterologous cells, raising
the possibility that dTrpA1 is a critical element of the
environmental temperature sensing apparatus. dTRPA1 is the
Drosophila ortholog of TRPA1, a protein with a critical
role in pain and inflammation in mammalian systems.Thus,
we anticipate that studies of dTRPA1 function and fly thermotaxis
will be relevant to mechanisms of sensory transduction and
animal behavior across a range of systems.
Having established the importance of dTrpA1 in heat avoidance,
we are continuing to investigate the thermosensory function
of the dTRPA1 channel and to further dissect the neuronal
circuitry for dTrpA1-dependent thermotaxis. We are also
pursuing both classical genetic and RNAi-based screening
approaches to identify regulators of dTRPA1 activity and
of thermotaxis.
Recent publications
P.A. Garrity. (2007) The role of adaptation in C. elegans
thermotaxis. J. Neurophysiology, in press.
J. Whited, M. Robichaux, J.C. Yang, and P.A. Garrity. (2007)
PTPMEG is required for the proper establishment and maintenance
of axon branches in the Drosophila central brain.
Development, 134, 43-53. [full
text]
R Khodosh, A. Augsburger, T.L. Schwarz, P.A. Garrity. (2006)
Bchs, a BEACH domain protein, antagonizes Rab11 in synapse
morphogenesis and other developmental events. Development,133,4655-65.
[full
text]
P.A. Garrity (2005). Tinkers to Evers to Chance: Semaphorin
signaling takes teamwork. Nature Neuroscience 8,
1635-1636. [full
text]
M. Rosenzweig, K. Brennan, T.D. Tayler, P.O. Phelps, A.
Patapoutian, and P.A. Garrity. (2005) The Drosophila ortholog
of TRPA1 regulates thermotaxis. Genes and Development
19:419-424. [abstract]
T.D. Tayler, M. Robichaux, and P.A. Garrity. (2004). Compartmentalization
of visual centers in the Drosophila brain requires Slit
and Robo proteins. Development 131:5935-5945. [abstract]
J. Whited, A. Cassell, M. Broulliette, and P.A. Garrity.
(2004). Dynactin is required to maintain nuclear position
within post-mitotic photoreceptor neurons. Development
131:4677-4686. [abstract]
P.A. Garrity (2003). How neurons avoid derailment. Nature
422, 570-571.
H.C. Sears, C.J. Kennedy, and P.A. Garrity. (2003). Macrophage-mediated
corpse engulfment is required for normal Drosophila CNS
morphogenesis. Development 130: 3557-3565. [abstract]
T. Tayler and P.A. Garrity (2003). Axon targeting in the
Drosophila visual system. Curr. Opinion Neurobiology
13, 90-95. [abstract]
J. Whited and P.A. Garrity (2002). Specifying axon identity
with Syd-1. Nature Neuroscience. 5, 1107-1108. [full
text]
M. Rosenzweig and P.A. Garrity (2002). Axon targeting meets
protein trafficking: Comm takes Robo to the cleaners. Dev.
Cell 3, 301-302. [abstract]
