Overview
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
Our work uses the visual and thermosensory systems of the fruit fly. These two systems each have particular advantages for the study of nervous system development and of behavior. The structure and organization of neurons in the fruit fly visual system are well characterized and present a wonderful system for understanding brain development. In particular, we are studying the mechanisms that control the morphogenesis of individual neurons and that control the grouping of neurons into specific processing centers within the brain. In contrast, the anatomy of the thermosensory system of the fly is largely unknown. However, our recent work suggests it will be a powerful system for investigating how sensory systems control behavior. We are using the fly to study how animals sense temperature and how gradations of a simple stimulus (temperature) are converted into a robust behavioral response (thermotaxis).

Neuronal Polarity and Nuclear Position: Neurons are highly polarized cells which extend processes specialized for receiving and transmitting information (dendrites and axons). The positioning of a neuron’s nucleus with respect to its axons and dendrites varies in a neuron-specific way and contributes to the great diversity of neuronal morphologies. We are using Drosophila photoreceptor neurons to understand how the position of the nucleus is determined as a neuron undergoes the morphological changes accompanying differentiation. Our work has shown 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). Reductions in Dynein and Dynactin activity cause a dramatic shift in the position of the photoreceptor nucleus. The nucleus moves away from the apical tip of the photoreceptor cell in the eye and travels down the path laid out by the axon into the brain. How do these microtubule motors control nuclear movement within the neuron? How is nuclear position normally coupled to the overall polarity of the neuron? The photoreceptors of the fly eye provide us with a powerful molecular genetic system for addressing these critical questions in neuronal cell biology.

Formation of Visual Processing Centers in the Fly Brain: The brain is not a homogeneous mixture of neurons and glia. Rather, neurons and glia are organized into discrete processing centers with specific functions. To understand the formation of complex brain structures, we are using the visual centers of the fly brain as a model system. The visual centers of the fly brain are comprised of four distinct processing centers that are built from two adjacent populations of progenitor cells that undergo extensive cell division and cell migration. Our goal is to identify the developmental mechanisms through which optic lobe neurons and glia are selectively grouped to form discrete processing centers.

We have recently identified the evolutionarily conserved guidance cue Slit and its Robo-family receptors as critical regulators of processing center morphogenesis (Tayler et al., 2004). These proteins act to maintain the distinct cellular compositions of the lamina and lobula processing centers, with the glial cells of the lamina producing Slit and the neurons of the developing lobula expressing multiple Robo receptors. The Slit protein associated with the lamina appears to repel the Robo-expressing neurons of the developing lobula, preventing lobula neurons from mixing with cells of the lamina. We want to understand the mechanisms that govern the highly selective distribution of Slit and Robo-family proteins within the visual system and how these proteins modulate cell movement to control processing center formation. Identifying the molecular mechanisms that govern region-specific cell affinities in the brain will be essential for explaining how the complex cytoarchitecture of the brain is established.

Thermosensory Behavior: A long-term goal of sensory system biology is to understand how sensory stimuli modulate animal behavior. One of the least understood of our senses is the sense of temperature. How is thermal energy converted into patterns of electrical activity that guide behavior? In my lab, we have begun to explore the thermosensory system of Drosophila larvae. While flies exhibit strong behavioral responses to temperature, very little was known about the molecules and neurons critical for thermotaxis, directed migration in response to differences in temperature. However, using behavioral assays and rapid molecular genetic screening approaches devised in our lab, we have recently identified the first regulator of Drosophila thermotaxis, the temperature-regulated TRP family ion channel dTRPA1 (Rosenzweig et al., 2005).  dTrpA1 is essential for larval avoidance of moderately elevated temperatures. Larvae lacking dTRPA1 fail to turn back when they encounter regions that are too warm, a behavioral defect with dire consequences. dTRPA1 is thus an attractive candidate to act as an environmental temperature sensor in the fly. We have also investigated the relationship between thermotaxis and other temperature-dependent behavior, such as rapid withdrawal from a higher temperature stimulus. Interestingly, we have found significant differences in the molecules and the neurons required for thermotactic avoidance of heat and for withdrawal from a high-temperature nociceptive stimulus, suggesting that these two behavioral responses are distinct (Rosenzweig et al., 2005). Our work implicates a previously unknown set of dTRPA1-expressing neurons as part of the circuit for thermotaxis.

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. Interestingly, in addition to a role in thermosensation, the vertebrate ortholog of dTRPA1 has also been proposed to be the long-sought mechanosensory channel required for hearing. 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.

Selected Publications
M.R. Rosenzweig, K.B. Brennan, K.B., T.D. Tayler, P.O. Phelps, A. Patapoutian, and P.A. Garrity. The Drosophila ortholog of vertebrate TRPA1 regulates thermotaxis. Genes Dev. 2005 Jan 28; (2005).

T.D. Tayler, M.B. Robichaux, and P.A. Garrity. Compartmentalization of visual centers in the Drosophila brain requires Slit and Robo proteins. Development 131, 5935-5945. (2004).

J.L. Whited, A. Cassell, M. Broulliette, and P.A. Garrity. Dynactin is required to maintain nuclear position within post-mitotic photoreceptor neurons.  Development 131,4677-4686. (2004). 

H.C. Sears, C.J. Kennedy, and P.A. Garrity. Macrophage-mediated corpse engulfment is required for normal Drosophila CNS morphogenesis. Development, 130, 3557-3565. (2003).

P.A. Garrity, C.H. Lee, I. Salecker, H.C. Robertson, C. Desai, K. Zinn, and S.L. Zipursky. Retinal axon target selection in Drosophila is regulated by a receptor protein tyrosine phosphatase. Neuron 22, 707-717. (1999).

P.A. Garrity, Y. Rao, I. Salecker, L. McGlade, T. Pawson, and S.L. Zipursky. Drosophila photoreceptor axon guidance and targeting require the Dreadlocks SH2/SH3 adapter protein. Cell 85, 639-650. (1996).

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