Smith Jean A.

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Smith
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Jean A.
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  • Article
    FXR1 splicing is important for muscle development and biomolecular condensates in muscle cells
    (Rockefeller University Press, 2020-03-13) Smith, Jean A. ; Curry, Ennessa G. ; Blue, R. Eric ; Roden, Christine ; Dundon, Samantha E.R. ; Rodríguez-Vargas, Anthony ; Jordan, Danielle C. ; Chen, Xiaomin ; Lyons, Shawn M. ; Crutchley, John M. ; Anderson, Paul ; Horb, Marko E. ; Gladfelter, Amy S. ; Giudice, Jimena
    Fragile-X mental retardation autosomal homologue-1 (FXR1) is a muscle-enriched RNA-binding protein. FXR1 depletion is perinatally lethal in mice, Xenopus, and zebrafish; however, the mechanisms driving these phenotypes remain unclear. The FXR1 gene undergoes alternative splicing, producing multiple protein isoforms and mis-splicing has been implicated in disease. Furthermore, mutations that cause frameshifts in muscle-specific isoforms result in congenital multi-minicore myopathy. We observed that FXR1 alternative splicing is pronounced in the serine- and arginine-rich intrinsically disordered domain; these domains are known to promote biomolecular condensation. Here, we show that tissue-specific splicing of fxr1 is required for Xenopus development and alters the disordered domain of FXR1. FXR1 isoforms vary in the formation of RNA-dependent biomolecular condensates in cells and in vitro. This work shows that regulation of tissue-specific splicing can influence FXR1 condensates in muscle development and how mis-splicing promotes disease.
  • Preprint
    mRNA structure determines specificity of a polyQ-driven phase separation
    ( 2018-04) Langdon, Erin M. ; Qiu, Yupeng ; Ghanbari Niaki, Amirhossein ; McLaughlin, Grace A. ; Weidmann, Chase ; Gerbich, Therese M. ; Smith, Jean A. ; Crutchley, John M. ; Termini, Christina M. ; Weeks, Kevin M. ; Myong, Sua ; Gladfelter, Amy S.
    RNA promotes liquid-liquid phase separation (LLPS) to build membrane-less compartments in cells. How distinct molecular compositions are established and maintained in these liquid compartments is unknown. Here we report that secondary structure allows mRNAs to self-associate and determines if an mRNA is recruited to or excluded from liquid compartments. The polyQ-protein Whi3 induces conformational changes in RNA structure and generates distinct molecular fluctuations depending on the RNA sequence. These data support a model in which structure-based, RNA-RNA interactions promote assembly of distinct droplets and protein-driven, conformational dynamics of the RNA maintain this identity. Thus, the shape of RNA can promote the formation and coexistence of the diverse array of RNA-rich liquid compartments found in a single cell.