Systems analysis of RNA trafficking in neural cells

Abstract In neural cells, certain RNAs are targeted to dendrites by a specific RNA trafficking pathway, termed the A2 pathway, mediated by the trans ‐acting trafficking factor, heterogeneous nuclear ribonucleoprotein (hnRNP) A2, which binds to an 11 nucleotide cis ‐acting trafficking sequence, termed the hnRNP A2 response element (A2RE). RNAs containing A2RE‐like sequences are recognized by hnRNP A2 in the nucleus and exported to the cytoplasm where they assemble into trafficking intermediates, termed granules, which also contain components of the translation machinery and molecular motors (cytoplasmic dynein and conventional kinesin). RNA granules move along microtubules to the cell periphery where they become localized and where the encoded protein is translated. Intracellular trafficking of RNA molecules by the A2 pathway is mediated by a complex system consisting of five different subsystems, ∼35 different molecules and ∼45 different molecular interactions. Specificity in the A2 pathway is provided by specific interactions of hnRNP A2 with different molecular partners in different subsystems. Polarity of RNA trafficking is controlled by transitions of trafficking intermediates between different subsystems. Comprehensive understanding of the A2 RNA trafficking pathway will require quantitative analysis of concentrations and diffusion constants for each of the different molecules, on rates and off rates for each of the different interactions, relevant conditional operators controlling specific interactions, and interactions of different subsystems. Once the necessary quantitative data are available, mathematical models for the different RNA trafficking subsystems can be developed using computational platforms such as the ‘Virtual Cell’. Here we describe how each of the subsystems in the A2 system functions and how the different subsystems interact to regulate RNA trafficking.