MassIVE MSV000089941

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The Pumilio1 brain region specific interactome reveals a direct connection with multiple RNA binding proteins suggesting two disease mechanisms

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Description

Mutations in the RNA-binding protein (RBP) Pumilio1 (PUM1) can cause dramatically different phenotypes. Mild mutations that reduce PUM1 levels by 25 percent lead to a mild, adult-onset ataxia, whereas heterozygous deletion or more severe mutations that reduce PUM1 levels 40-60 percent produce an infantile syndrome involving multiple developmental delays and seizures. Why this difference in expression should cause such different phenotypes has been unclear; known PUM1 targets are de-repressed to equal degrees in both diseases. We therefore sought to map PUM1s interactome in specific murine brain-regions. We identified a number of putative interactors involved in different aspects of RNA metabolism such as silencing, alternative splicing, and polyadenylation. We find that PUM1 haploinsufficiency alters the stability of several interactors and disrupts the regulation of targets of those interactors, whereas mild PUM1 loss only de-represses PUM1-specific targets. We validated these phenomena in patient-derived cell lines and show that normalizing PUM1 levels rescues the levels of interactors and their targets. We therefore propose that dosage sensitivity does not necessarily reflect a linear change in levels but can involve distinct mechanisms. Studying the interactors of RBPs in vivo will be necessary to understand their functions in neurological diseases. [doi:10.25345/C52R3P18F] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: Rna binding proteins, Pumillio, brain

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Principal Investigators:
(in alphabetical order) 		Marko Jovanovic, Columbia University, USA
Submitting User: mj2794
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