Deciphering the role of RNA-binding proteins in neurodevelopment and disease

🔍Interactive diagrams for RNA regulation, Translational Control and Protein Synthesis: https://cst-science.com/zj6a2l

Participating experts: Michael A. Kiebler, PhD (Ludwig-Maximilians University-Munich), and Chaolin Zhang, PhD (Columbia University)

Investigating RNA-binding proteins (RBPs) and their effect on translation has become increasingly important for understanding neurodevelopment and neurodegenerative diseases. The posttranscriptional regulation of RNA via RBPs can have a profound impact on when, where, and how messenger RNA translation occurs within cells, including neurons. However, the mechanistic role that RBPs play in disease progression has not been fully defined. Recently developed high-throughput sequencing techniques have enabled mapping of in vivo protein–RNA interactions on a genome-wide scale down to single-nucleotide resolution. Studies using an integrative analysis of splicing-regulatory networks have led to the identification of hundreds of alternative exons that are controlled by specific neuronal RBPs. Additional work has shed light on how RBPs, including Staufen2 (Stau2) and Pumilio2 (Pum2), regulate protein translation and localization at individual neuronal synapses. Continued research into how localized protein synthesis contributes to morphological and functional changes in neurons will provide a better understanding of learning, memory, and neurodegenerative disease mechanisms. In this webinar, the speakers will discuss ways to analyze neuron-specific RBPs and RNA transcripts and to examine the effects of their well-regulated translation at synapses.

During the webinar, viewers will:

● Learn how RBPs target and interact with specific RNA transcripts
● Gain insight into how RBPs influence neuron-specific alternative splicing
● Explore how specific RNA-regulatory networks can affect learning and memory

Contents:

0:00 Introduction
2:53 RNA-binding proteins and their role at the synapse
3:23 From DNA to protein in a eukaryote
4:38 RNA on the way to the synapse
6:00 Experimental evidence for RNA localization in the CNS
6:40 Selected RBPs are excellent markers to follow RNA transport in hippocampal neurons
9:27 Staufen2 undergoes co-transport with MS2+Rgs4 3'UTR reporter mRNA
11:05 Local glutamate stimulation triggers mRNA recruitment in to the dendritic spine
14:06 Assembly of RNA granules - who is in charge, the RNA or the RBP?
16:10 Getting rid of the RNA in granules
17:26 RNA drives physiological granule assembly in neurons
18:19 Artificially overexpressing RNA causes large aggregates/condensates to form
19:44 A well-defined RNA duplex recruits Stau2 to RNA granules in neurons
24:36 RNA regulatory mechanisms underlying neuronal development and cell type diversity
25:28 Alternative splicing is a major driver of molecular diversity
26:58 The brain has a unique RNA regulatory program
28:32 Integrative analysis of splicing-regulatory networks
30:58 Path to a comprehensive view of regulation
31:59 Brain-neuron specific splicing is established during development
32:31 Splicing factors driving developmental splicing switches
35:45 Different neuronal subtypes have distinct splicing regulation
39:25 Establishing a Rbfox1-3 triple knockout model
40:48 Rbfox triple KO neurons show reduced excitability
41:37 Rbfox tKO neurons show impaired AIS
43:30 Rbfox regulates many genes encoding AIS components
44:49 Forced expression of AnkG embryonic form have AIS defects
48:36 How does clustering of cell types by splicing compare to clustering for RNA-seq?
51:51 What triggers localized translation of RNAs once they are transported to synapses?
53:28 When RNP granules change direction, do they switch motors?
55:12 Do you envision development of inhibitors to RNA binding/splicing factors as therapeutic targets?
56:35 Does one RBP bind to one mRNA at one site, or several sites, or bind multiple mRNA's?
58:31 Any updates on how many RNA molecules are in RNA granules?


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