Whole cell response to receptor stimulation involves many deep and distributed subcellular processes

Abstract

Neurite outgrowth is an integrated whole cell process that represents the earliest steps in neuronal differentiation. We studied cannabinoid-1 receptor regulated neurite outgrowth to identify the different subcellular processes (SCPs) involved and how they come together to produce a whole cell response. We identified the genes that were differentially expressed after CB1 receptor stimulation. From the differentially expressed components we identified the SCPs involved and how the SCPs connect to one another both horizontally and vertically. We used these SCP networks to identify genes, which when knocked down would validate the involvement of the SCP in neurite outgrowth. We identified a varied list of SCPs including those involved in pyrimidine metabolism, lipid biosynthesis, mitochondrial transport function, mRNA splicing and stability in addition to those involved in membrane vesicle production, transport and fusion and microtubule dynamics. Overall these data and computational analyses show that the downstream SCPs required for neurite outgrowth are widely distributed and involve a range of normal cellular functions. Additionally, several of these processes can be considered distal in terms of their proximity to cell signaling pathways and the microtubule and membrane vesicle dynamics, the proximal SCPs required for neurite outgrowth. Hence we conclude that receptor regulation of neurite outgrowth is distributed and deep.