The formation of functional neural circuits requires the proper migration of newly generated neurons, precise guidance of axons to the appropriate postsynaptic targets, the formation of elaborate dendritic arbors and establishment of synaptic connections. These processes depend on the reiterative use of cell-surface receptors throughout development that respond to instructive cues present in the extracellular environment. The transmembrane glycoprotein dystroglycan is involved in multiple aspects of neural circuit development, including axon guidance and dendritic arborization. The objective of this proposal is to define the specific molecular pathways that dystroglycan functions within to regulate these processes.
The first aim tests the hypothesis that dystroglycan interacts with the planar cell polarity (PCP) protein Celsr3 to regulate axon guidance. The experiments proposed in this aim will define which cellular populations dystroglycan functions in to regulate axon guidance in vivo, determine how dystroglycan and Celsr3 interact in vitro and in vivo and investigate how the loss of dystroglycan affects signaling downstream of PCP pathway activation.
The second aim will focus on understanding the role of dystroglycan in regulating dendritic arborization. Specifically, the experiments outlined will examine how dendritic morphology is affected in models of dystroglycanopathy, determine if dystroglycan functions cell-autonomously and provide mechanistic insight into the intracellular signaling cascades downstream of dystroglycan that regulate dendritic morphology. Taken together, the proposed experiments will define the role of dystroglycan in regulating multiple aspects of neural circuit development and provide insight into how these processes are affected in individuals with mutations that affect normal dystroglycan function.
Mutations affecting the function of dystroglycan cause a form of congenital muscular dystrophy (CMD) that is frequently associated with a range of neurodevelopmental defects. The proposed studies use genetic and biochemical approaches to define the role of dystroglycan in regulating neural circuit development and elucidate the mechanistic basis for how dystroglycan regulates axon guidance and dendritic arborization.
| Vahedi-Hunter, Tyler A; Estep, Jason A; Rosette, Kylee A et al. (2018) Cas Adaptor Proteins Coordinate Sensory Axon Fasciculation. Sci Rep 8:5996 |
| Clements, Reena; Wright, Kevin M (2018) Retinal ganglion cell axon sorting at the optic chiasm requires dystroglycan. Dev Biol 442:210-219 |
| Clements, Reena; Turk, Rolf; Campbell, Kevin P et al. (2017) Dystroglycan Maintains Inner Limiting Membrane Integrity to Coordinate Retinal Development. J Neurosci 37:8559-8574 |
