Rejji Kuruvilla is an associate professor of biology whose research focuses on endocytic trafficking of neurotrophins in nervous system development and maintenance. She received her BS from Calcutta University in India, her PhD from the University of Houston, and did her postdoctoral work at Johns Hopkins University School of Medicine.
Endocytic trafficking of neurotrophins in nervous system development and maintenance
In the nervous system, communication between neurons and their post-synaptic target cells, often located millimeters or even meters away from the neuronal cell bodies, is critical for the formation, refinement and maintenance of functional neuronal connections. Diffusible signals secreted by target tissues impinge on nerve terminals to influence diverse aspects of neural development and maintenance, including neuronal survival, axon growth, target innervation, synapse formation and stability. The family of neurotrophins provides one of the best examples of these target-derived instructive cues. Neurons are highly polarized cells that pose a formidable challenge for growth factor signaling. A unique aspect of neurotrophin signaling is that although neurotrophins bind their Trk receptors on axons, they must control transcription and other cellular processes that take place long distances away in the cell body. In some cases, this distance may be 1000-fold greater than the diameter of the cell body. Thus, a fundamental cell biological question is to understand how target-derived neurotrophins acting locally on nerve terminals effect changes in gene expression in remote neuronal cell bodies. Currently, numerous lines of evidence support a model in which neurotrophins released from targets are endocytosed in nerve terminals and retrogradely transported in signaling endosomes back to the cell bodies. Perturbations in the endocytosis and long-distance transport of neurotrophins are thought to contribute to the pathogenesis of neurodevelopmental and neurodegenerative disorders such as Down Syndrome, Huntington’s Disease and Alzheimer’s Disease.
A key focus of my laboratory is to investigate how neurotrophins coordinate neuronal development and the maintenance of adult neurons by regulating the endocytic and trafficking machinery in neurons. We use a combination of live imaging, biochemical and electron microscopic assays to investigate molecular mechanisms of endocytosis, recycling and long-distance axonal transport of neurotrophins and their receptors in neurons. During endocytic trafficking in neurons, neurotrophin receptors are not passive passengers being carried along by a constitutively operating endocytic machinery, rather, neurotrophin signaling actively modulates the endocytic machinery to drive their own trafficking. Thus, we are also investigating the molecular mechanims underlying the interplay between neurotrophin signaling and endocytosis.
Role of sympathetic innervation in pancreas development
The sympathetic nervous system, a branch of the autonomic nervous system, is critical for organ homeostasis. Postganglionic sympathetic neurons innervate a variety of peripheral targets to regulate several physiological processes including blood glucose levels, cardiac output and body temperature. Sympathetic dysfunction is associated with prevalent diseases including peripheral neuropathies, diabetes and congestive heart failure, which may originate from developmental perturbations in the innervation of sympathetic target tissues. The sympathetic nervous system develops in parallel with the organogenesis of innervated peripheral tissues. While it is well established that, during development, sympathetic neurons rely on target-derived signals for survival and growth, surprisingly little is known about the reciprocal contribution of sympathetic innervation to the morphogenesis of a target tissue. Pancreatic islets of Langerhans, the functional units in the regulation of glucose homeostasis, are richly innervated by sympathetic fibers. While neural activity is known to modulate hormone release in adult islets, the contribution of sympathetic innervation to pancreatic organogenesis remains unknown.
We recently found that sympathetic innervation is necessary for the formation of the pancreatic islets of Langerhans and for their functional maturation. Genetic or pharmacological ablation of sympathetic innervation during development resulted in altered islet architecture, reduced insulin secretion and impaired glucose tolerance in mice. Similar defects were observed with pharmacological blockade of β-adrenergic signaling. Conversely, the administration of a β-adrenergic agonist restored islet morphology and glucose tolerance in de-innervated animals. Furthermore, in neuron-islet co-cultures, sympathetic neurons promoted islet cell migration in a β-adrenergic dependent manner. Our study reveals that islet architecture requires extrinsic inductive cues from neighboring tissues such as sympathetic nerves, and suggests that early perturbations in sympathetic innervation might underlie metabolic disorders.
The immediate directions for this project are to identify the nerve-derived signals and characterize the signaling pathways activated in islet cells that regulate islet structure and acquisition of functional maturation. These studies will provide new insight into islet development, and will have important implications for current translational efforts to identify factors critical for the onset of pancreatic dysfunction.
Ami Patel, Naoya Yamashita, Maria Ascaño, Daniel Bodmer, Erica Boehm, Chantal Bodkin-Clarke, Yun Kyoung Ryu, and Rejji Kuruvilla. RCAN1 links impaired neurotrophin trafficking to aberrant development of the sympathetic nervous system in Down syndrome. Nature Communications, in press
Wang G, Rajpurohit SK, Delaspre F, Walker SL, White DT, Ceasrine A, Kuruvilla R, Li RJ, Shim JS, Liu JO, Parsons MJ, Mumm JS. First quantitative high-throughput screen in zebrafish identifies novel pathways for increasing pancreatic β-cell mass. 2015. Elife. Jul 28;4.
Jessica Houtz and Rejji Kuruvilla. VIP pipes up: neuronal signals direct tubulogenesis. 2014. Dev Cell. Aug 25;30(4):361-2.
Philip Borden, Jessica Houtz, Steven D. Leach, Rejji Kuruvilla. Sympathetic innervation during development is necessary for pancreatic islet architecture and functional maturation. Cell Reports. 2013. July 25;4(2):287-301.
Shih-Kuo Chen, Kylie S. Chew, David S. McNeill, Patrick W. Keeley, Jennifer L. Ecker, Buqing Q. Mao, Johan Pahlberg, Bright Kim, Sammy C.S. Lee, Michael Fox, William Guido, Kwoon Y. Wong, Alapakkam P. Sampath, Benjamin E. Reese, Rejji Kuruvilla,* and Samer Hattar*. Apoptosis regulates ipRGC spacing necessary for rods and cones to drive circadian photoentrainment. Neuron. 2013 Feb 6;77(3):503-15.
Yun Kyoung Ryu, King Yu Lo, Sarah Collins, Haiqing Zhao* and Rejji Kuruvilla*. An autocrine Wnt5a-Ror signaling loop mediates sympathetic target innervation. Developmental Biology. 2013 Feb 27.
Oscar Marcelo Lazo, Andres Gonzalez, Maria Ascano, Rejji Kuruvilla, Andres Couve, and Francisca Bronfman. BDNF regulates Rab11-mediated recycling endosome dynamics to induce dendritic branching. J. Neuroscience. 2013. Apr 3;33(14):6112-22.
Henry Ho, Michael Susman, Jay Bikoff, Yun Kyoung Ryu, Andrea Jonas, Linda Hu, Rejji Kuruvilla and Michael E. Greenberg. Wnt5a-Ror-Dishevelled signaling constitutes a core developmental pathway that controls tissue morphogenesis. Proc Natl Acad Sci U S A. 2012 Mar 13;109(11):4044-51. Epub 2012 Feb 17
Maria Ascano, Daniel Bodmer and Rejji Kuruvilla. Endocytic trafficking of neurotrophins in neural development. Trends Cell Biol. 2012 Mar 21. [Epub ahead of print]
Daniel Bodmer*, Maria Ascaño* and Rejji Kuruvilla, 2011. Isoform-specific dephosphorylation of dynamin1 by calcineurin couples neurotrophin receptor endocytosis to axonal growth. Neuron 70, 1085-1099.
* Equal authors.
Alissa Armstrong, Yun Kyoung Ryu, Deanna Chieco and Rejji Kuruvilla. 2011. Frizzled3 is required for neurogenesis and target innervation during sympathetic nervous system development. J. Neuroscience31 (7):2371–2381
Maria Ascaño, Alissa Richmond, Philip Borden, and Rejji Kuruvilla. 2009. Axonal Targeting of Trk Receptors via Transcytosis Regulates Sensitivity to Neurotrophin Responses. J. Neuroscience 29:11674-11685
Daniel Bodmer, Seamus Levine-Wilkinson, Alissa Richmond, Sarah Hirsh and Rejji Kuruvilla, 2009.Wnt5a mediates NGF-dependent axonal branching and growth in developing sympathetic neurons. J. Neuroscience 29 (23):7569-7581
Larry S. Zweifel, Rejji Kuruvilla, and David D. Ginty, 2005. Functions and Mechanisms of Retrograde Neurotrophin Signaling. Nature Reviews Neuroscience 6, 615-625.
Gregorio Valdez, Wendy Akmentin, Polyxeni Philippidou, Rejji Kuruvilla, David D. Ginty and Simon Halegoua, 2005. Pincher-mediated macroendocytosis underlies retrograde signaling by neurotrophin receptors. J. Neuroscience 25 (21), 5236-5247.
Xi Chen, Haihong Ye, Rejji Kuruvilla, Narendrakumar Ramanan, Katherine W. Scangos, Chao Zhan, Nicolas M. Johnson1, 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.
* Equal authors.
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.
* Equal authors.
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.
Naoya Yamashita, Ph.D