Post-transcriptional regulation by RNA-binding proteins (RBPs) underlies many processes critical for proper neuronal function. Dysregulation of the brain-enriched RBP Rbfox1 has been linked to serious neurological diseases such as epilepsy and autism spectrum disorders. While Rbfox1 regulation of synaptic function is thought to contribute to these diseases, efforts to understand how RNA-level changes affect neuronal physiology remain in their infancy, and the mechanism of Rbfox1 regulation is not yet well understood. The long-term goal of understanding complex neurological diseases will require careful investigation of Rbfox1 regulation of synaptic function at the cellular and molecular level We have identified an Rbfox1 target, Vamp1, which may be involved in inhibitory synaptic transmission. We hypothesize that Rbfox1 controls neuronal excitability by regulating Vamp1 at the post-transcriptional level in a cell-type specific manner. We will combine electrophysiological and biochemical approaches in mouse neurons to 1) Determine the function of Vamp1 in the Rbfox1 knockout and 2) Define the mechanism by which Rbfox1 regulates Vamp1 transcript levels. These studies will provide mechanistic insight into Rbfox1 function and cell- type specific post-transcriptional regulation and lay the foundation for understanding the molecular basis of serious neurological diseases.
Rbfox1 is a post-transcriptional regulator that has been associated with human epilepsy and autism spectrum disorders. In this research proposal I will combine biochemical and electrophysiological approaches to examine the role of Rbfox1 in regulating synaptic function at the RNA level. These studies will advance our knowledge of Rbfox1 function in the brain at a cellular and molecular level and provide a foundation for targeted and effective therapeutics for serious neurological diseases.
|Vuong, Celine K; Wei, Weizheng; Lee, Ji-Ann et al. (2018) Rbfox1 Regulates Synaptic Transmission through the Inhibitory Neuron-Specific vSNARE Vamp1. Neuron 98:127-141.e7|
|Ying, Yi; Wang, Xiao-Jun; Vuong, Celine K et al. (2017) Splicing Activation by Rbfox Requires Self-Aggregation through Its Tyrosine-Rich Domain. Cell 170:312-323.e10|
|Vuong, Celine K; Black, Douglas L; Zheng, Sika (2016) The neurogenetics of alternative splicing. Nat Rev Neurosci 17:265-81|