Meet me at the ER: Exploring inter-organelle communication in neurons

Membrane-bound and membraneless organelles ensure compartmentalization of incompatible biochemical reactions into distinct compartment of eukaryotic cells. It has been increasingly recognized that organelles form dynamic contact with each other to regulate organelle dynamic and positioning in coordination with cytoskeleton. Intracellular organization is crucial for proper cellular functioning in all cell types, especially in morphologically complex neurons. Neurons are highly polarized cells defined with two morphologically and functionally distinct compartments- somatodendritic and axonal compartments. Neuronal polarity relies on careful coordination of proper organelle segregation and spatiotemporal regulation of neuronal proteome, that is essential for neuron development and functions. Organelle crosstalk might provide platforms for organelle transport, organelle dynamics, organelle organization and specific local functions in neurons. Although organelle communication has been previously reported in neurons, still little is known about the organelle contact and their local functions in neurons. In chapter 2, we first discuss the current knowledge about organelle communications in non-neuronal cells and highlight the gaps in knowledge in polarized neurons. In chapter 3, we report ER – lysosome contacts in the neuronal soma, enriched in a pre-axonal region preceding the axon initial segment (AIS). We demonstrate that ER – lysosome contact provides a platform for lysosome motility, fission and axonal translocation. In chapter 4, we report a complex interplay between ER – lysosome – RNA granules. These three-way contacts regulate RNA granule dynamics and transport. Finally in chapter 5, we demonstrate that axonal ER tubules interact with ribosomes to regulate local axonal translation, which is essential for neuronal development. Altogether, the findings in this thesis support a model in which the neuronal ER – organelle interactions could provide a platform for specific local functions, essential to regulate neuronal development and functions.