Catherine Collins - US grants

"This award is funded under the American Recovery and Reinvestment Act of 2009
(Public Law 111-5)."

Neurons transmit electrical information through long axons to distant parts of the brain and body. The cell bodies of neurons must also receive information from their targets, however very little is known about how this "retrograde" information is transmitted. Microtubule based axonal transport machinery, comprised of kinesin and dynein motor proteins, plays a critical role in axonal signaling pathways. The goal of this study is to identify how different signaling molecules are carried by motor proteins in axons. It will compare the mechanisms for two different axonal signaling pathways that function within the same neuron. It takes advantage of powerful genetics in Drosophila and the simple anatomy of the larval motoneuron, which allows observation of both signal transduction and axonal transport within a single cell in a living animal. The results should identify molecules and interactions that function in the thus far poorly understood process of retrograde signaling, a process that is important for the formation of neuronal circuits during development and their modification during learning and memory. This project will support the training of one graduate student and two undergraduate students, and has an outreach component that exposes girls in middle school to genetics, microscopy, and contemporary questions in the field of neurodevelopment.

DESCRIPTION (provided by applicant): An important goal for regenerative medicine is to understand how neurons sense and respond to axonal damage. Due to the highly polarized structure of axons, axonal transport machinery, which delivers cellular cargo from one part of the axon to the other, plays important roles in the cellular responses to injury. One major response is the induction of new axonal growth. This regenerative response requires the retrograde transport of signaling molecules from the injury site to the nucleus. Another major response is degeneration of the severed distal 'stump'. This may also rely on axonal transport machinery, since defects in the process of axonal transport usually accompany (and often proceed) axonal degeneration in neurodegenerative disorders. To study mechanisms of injury signaling, degeneration, and axonal transport, we take advantage of the powerful genetics of Drosophila as a model organism, in which we have developed a new injury paradigm that allows mechanistic characterization of injury response pathways in vivo. Our assays include nuclear reporters, which measure changes in gene expression in injured neurons, and live imaging assays that measure axonal transport of specific cargo in axons. The focus of this study is the role and mechanism of a conserved axonal kinase, named Wallenda (Wnd) in Drosophila, DLK in vertebrates. Recent studies indicate that this kinase regulates both regenerative and degenerative responses to axonal injury. Our recent observations suggest that Wnd may function by regulating the transport of specific cargo in axons. The goals of this study are to identify the Wnd-regulated cargo, and determine the role(s) of this cargo in both retrograde signaling and degeneration. PUBLIC HEALTH RELEVANCE: Axonal damage triggers both regenerative and degenerative responses in neurons. We are studying a molecular pathway, which has recently been discovered to function in both the regrowth of axons after injury and also in degeneration of the part of the axon that has been severed from the cell body. The findings from this work will be important both for treatment of spinal cord injuries and also for understanding mechanisms of neurodegenerative disorders.