Axon branching allows a neuron to communicate with multiple partners and helps establish morphologically and functionally distinct neural networks. To ensure proper synaptic connections, branching is tightly regulated by signaling pathways that allow environmental cues to instruct axons when and where to make branches. The long term goal of the proposed research is to investigate the molecular and cellular basis of this regulation, understand how it contributes to the initial development and the subsequent plastic rearrangement of synaptic connections, and provide insights into how to regenerate new branches and functional connections after injury. Using the development of stereotypic axonal branches of rodent sensory neurons from the dorsal root ganglion and trigeminal ganglion as models, we have identified an extracellular signaling pathway involving the secreted molecule Slit in promoting axon branching. In addition, our preliminary studies have demonstrated that the cGMP pathway provides an intracellular signaling mechanism for branching regulation. Using primary sensory neuron cultures and knockout mice, we propose the following three aims to further characterize the role of cGMP signaling: 1) use in vivo analysis to establish cGMP signaling as a general signaling mechanism in regulating the development of diverse yet stereotypic sensory axon branches;2) identify the downstream signaling mechanism mediating the cGMP activity in sensory axon branching;3) determine the cellular mechanism underlying the spatial and temporal control of axon branching.
These aims should help establish a distinct signaling pathway in regulating axon branching and fill in a major gap in our understanding of an important process in making synaptic connections. In addition, since loss of synaptic stability is the hallmark of many neurological disorders, our study of this fundamental process should provide new insights into the etiology of these diseases.
The goal of the proposed research is to investigate the molecular and cellular basis of axon branching, an important process in making synaptic connections and establishing neural networks. We will use a combination of molecular, cellular and genetic approaches to characterize key molecular pathways and identify the signaling mechanisms underlying the regulation of axon branching. The knowledge obtained from this study will not only help understand brain development, but also provide new insights into the molecular basis of many neurological disorders as well as how to promote nerve regeneration after stroke and injury.
|Tymanskyj, Stephen R; Yang, Benjamin; Falnikar, Aditi et al. (2017) MAP7 Regulates Axon Collateral Branch Development in Dorsal Root Ganglion Neurons. J Neurosci 37:1648-1661|
|Kim, Young J; Wang, Sheng-zhi; Tymanskyj, Stephen et al. (2016) Dcc Mediates Functional Assembly of Peripheral Auditory Circuits. Sci Rep 6:23799|
|Rama, Nicolas; Dubrac, Alexandre; Mathivet, Thomas et al. (2015) Slit2 signaling through Robo1 and Robo2 is required for retinal neovascularization. Nat Med 21:483-91|
|Zuhdi, Nora; Ortega, Blanca; Giovannone, Dion et al. (2015) Slit molecules prevent entrance of trunk neural crest cells in developing gut. Int J Dev Neurosci 41:8-16|
|Lu, Cindy C; Cao, Xiao-Jie; Wright, Samantha et al. (2014) Mutation of Npr2 leads to blurred tonotopic organization of central auditory circuits in mice. PLoS Genet 10:e1004823|
|Gibson, Daniel A; Tymanskyj, Stephen; Yuan, Rachel C et al. (2014) Dendrite self-avoidance requires cell-autonomous slit/robo signaling in cerebellar purkinje cells. Neuron 81:1040-1056|
|Domyan, Eric Thomas; Branchfield, Kelsey; Gibson, Daniel A et al. (2013) Roundabout receptors are critical for foregut separation from the body wall. Dev Cell 24:52-63|
|Wang, Sheng-zhi; Ibrahim, Leena A; Kim, Young J et al. (2013) Slit/Robo signaling mediates spatial positioning of spiral ganglion neurons during development of cochlear innervation. J Neurosci 33:12242-54|
|Xia, Caihong; Nguyen, Minh; Garrison, Amy K et al. (2013) CNP/cGMP signaling regulates axon branching and growth by modulating microtubule polymerization. Dev Neurobiol 73:673-87|
|Wright, Kevin M; Lyon, Krissy A; Leung, Haiwen et al. (2012) Dystroglycan organizes axon guidance cue localization and axonal pathfinding. Neuron 76:931-44|
Showing the most recent 10 out of 19 publications