[Research Interests] [Representative Publications] RESEARCH INTERESTSThe proper functioning of the nervous system relies on the establishment of precise neuronal circuits. These neuronal circuits are largely formed during early development. To form functional neuronal circuits, neurons receive specific information in the form of extracellular cues from the target tissues that they innervate. To date, the family of neurotrophins provides the best example of these target-derived instructive cues that regulate diverse developmental events in the vertebrate nervous system, including survival, axonal and dendritic growth and synapse formation. Interest in understanding the biology of neurotrophins remains unabated due to their association with a wide spectrum of human diseases ranging from developmental disorders such as neuroblastoma and hereditary neuropathies, to psychiatric and neurological disorders in adults. We are employing molecular, cellular and genetic approaches to address fundamental aspects of neurotrophin signaling and function in neurons: I. Regulation of neuronal development by trafficking of neurotrophins and their receptors: For decades, it has been known that neurotrophins and their receptors undergo long-range trafficking in neurons, but how neurotrophins utilize the trafficking machinery to regulate distinct aspects of neuronal development remains poorly characterized. Our long-term goal is to gain insight into how neurotrophins coordinate neuronal development by regulating the cell’s endocytic machinery. Using a combination of fluorescent, biochemical and electron microscopic assays, we are investigating molecular mechanisms of endocytosis, recycling and axonal transport of neurotrophins and their receptors in developing neurons. We are employing structure-function analyses to identify endocytic motifs in the neurotrophin receptors, the Trk receptor tyrosine kinases, that mediate distinct aspects of receptor trafficking. Finally, we are assessing the role of distinct modes of Trk trafficking on neurotrophin-dependent survival, axonal growth and neuronal morphology. II. Identification of local and retrograde signaling mechanisms underlying neurotrophin-mediated axonal growth: A second project in the lab is focused on investigating the intracellular signaling pathways by which target-derived neurotrophins regulate multiple stages of axonal growth including axon initiation, projection along intermediate targets and innervation of final target tissues. We are employing in vitro and in vivo approaches to dissect the local signaling pathways activated in axon terminals, as well as transcriptional programs activated in remote neuronal soma by target-derived neurotrophins, that mediate unique aspects of axonal growth and morphology. REPRESENTATIVE PUBLICATIONSChen, X., Haihong, Y., Kuruvilla R., Ramanan, N., Scangos, K.W., Zhan, C., Nicolas M. Johnson, N.M., Pamela M. England, Kevan M. Shokat and David D. Ginty. 2005. A chemical–genetic approach to studying neurotrophin signaling. Neuron 46, 13-21. Rejji Kuruvilla * , Larry Zweifel * , Natalia Glebova, Bonnie Lonze, Haihong Ye and David Ginty. 2004. A neurotrophin signaling cascade coordinates sympathetic neuron development through differential control of TrkA trafficking and retrograde signaling. Cell 118, 1-20. Haihong Ye * , Rejji Kuruvilla * , Larry Zweifel and David Ginty. 2003. Evidence in support of signaling endosome-based retrograde survival of sympathetic neurons . Neuron 39, 57-68. Cristinel Miinea, Rejji Kuruvilla, Houra Merrikh and Joseph Eichberg. 2002. Altered arachidonic acid biosynthesis and antioxidant protection mechanisms in Schwann cells grown in elevated glucose. J. Neurochem . 81:1253-1262. Rejji Kuruvilla, Haihong Ye and David Ginty. 2000. Spatially and functionally distinct roles of the PI3-K effector pathway during NGF signaling in sympathetic neurons. Neuron 27:499-512. Rejji Kuruvilla and Joseph Eichberg. 1998. Depletion of phospholipid arachidonoyl-containing molecular species in a human Schwann cell line grown in elevated glucose and their restoration by an aldose reductase inhibitor. J. Neurochem . 71:775-783. Invited Reviews: 1. Larry S. Zweifel, Rejji Kuruvilla, and David D. Ginty. 2005. Functions and Mechanisms of Retrograde Neurotrophin Signaling. Nature Reviews Neuroscience. 6:615-625. Review. Lab MembersPostdoctoral Fellow: Graduate Students: Undergraduate Students:
|
