Neurons are exceptionally polar – their different parts possess utterly distinct structural and functional attributes. Axons and dendrites are two such polar specialisations, whose segregation early in development depends upon alternative splicing (AS) of key mRNAs. How AS contributes to the subsequent maintenance of neuronal polarity, however, remains unknown. To answer this question, this project will use state-of-the-art bioinformatic, molecular and neurophysiological tools at the single-cell level. We will leverage natural variation within a distinct neuronal population to understand how AS can influence neuronal polarity across time and space, gaining fundamental insight into processes that are crucial for normal brain function.
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Yap K, Xiao Y, Friedman BA, Je HS, and Makeyev EV (2016) Polarizing the Neuron through Sustained Co-expression of Alternatively Spliced Isoforms. Cell Rep. 15:1316-1328.
Hamid FM and Makeyev EV (2017) A mechanism underlying position-specific regulation of alternative splicing. Nucleic Acids Res 45:12455-12468.
Chand AN, Galliano E, Chesters RA, Grubb MS (2015) A distinct subtype of dopaminergic interneuron displays inverted structural plasticity at the axon initial segment. J Neurosci, 35:1573-90.
Yap K, Mukhina S, Zhang G, Tan JSC, Ong HS, and Makeyev EV (2018) A Short Tandem Repeat-Enriched RNA Assembles a Nuclear Compartment to Control Alternative Splicing and Promote Cell Survival. Mol Cell 72:525-540.