Fragile X Related Protein-1 (FXR1) Regulates RNA Metabolism in Striated Muscle

Persistent Link:
http://hdl.handle.net/10150/195153
Title:
Fragile X Related Protein-1 (FXR1) Regulates RNA Metabolism in Striated Muscle
Author:
Whitman, Samantha
Issue Date:
2011
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Cardiac muscle function necessitates the meticulous assembly and interactions of several cytoskeletal and regulatory proteins into specialized structures that orchestrate contraction and transmission forces. Despite extensive studies identifying the protein components responsible for these important aspects of heart development, putative RNA based mechanisms remain poorly understood, even with their demonstrated importance in other tissues. Evidence suggests that post-transcriptional regulation is critical for muscle function, but the molecular players involved (RNA binding proteins and mRNA targets) have remained elusive. We investigated the molecular mechanisms and targets of the muscle-specific Fragile X Related protein-1 (FXR1), an RNA binding protein whose absence leads to perinatal lethality in mice. Loss of FXR1 results in global protein level alterations. Morphological and biochemical analyses of Fxr1^(-/-) mice revealed severe disruption of intercalated disc and costamere architecture and composition. We identified several candidate mRNAs specifically enriched in the FXR1 protein complex. Two targets that likely contribute to the architectural defects are desmoplakin (dsp) and talin2 (tln2). In vitro assays indicate that FXR1 binds to these mRNA targets directly and represses their translation. Additionally, we provide preliminary evidence that the Fxr1^(-/-) mice mimic a hypothyroid state of cardiac gene expression, with alterations in myosin heavy chain and troponin I isoforms. Our findings reveal the first mRNA targets of FXR1 in muscle and support translational repression as a novel mechanism for cardiac muscle development and function.
Type:
text; Electronic Dissertation
Keywords:
FXR1; Heart; Muscle; RNA; RNA-binding protein; Translation
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Cell Biology & Anatomy; Graduate College
Degree Grantor:
University of Arizona
Advisor:
Gregorio, Carol C
Committee Chair:
Gregorio, Carol C

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleFragile X Related Protein-1 (FXR1) Regulates RNA Metabolism in Striated Muscleen_US
dc.creatorWhitman, Samanthaen_US
dc.contributor.authorWhitman, Samanthaen_US
dc.date.issued2011en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractCardiac muscle function necessitates the meticulous assembly and interactions of several cytoskeletal and regulatory proteins into specialized structures that orchestrate contraction and transmission forces. Despite extensive studies identifying the protein components responsible for these important aspects of heart development, putative RNA based mechanisms remain poorly understood, even with their demonstrated importance in other tissues. Evidence suggests that post-transcriptional regulation is critical for muscle function, but the molecular players involved (RNA binding proteins and mRNA targets) have remained elusive. We investigated the molecular mechanisms and targets of the muscle-specific Fragile X Related protein-1 (FXR1), an RNA binding protein whose absence leads to perinatal lethality in mice. Loss of FXR1 results in global protein level alterations. Morphological and biochemical analyses of Fxr1^(-/-) mice revealed severe disruption of intercalated disc and costamere architecture and composition. We identified several candidate mRNAs specifically enriched in the FXR1 protein complex. Two targets that likely contribute to the architectural defects are desmoplakin (dsp) and talin2 (tln2). In vitro assays indicate that FXR1 binds to these mRNA targets directly and represses their translation. Additionally, we provide preliminary evidence that the Fxr1^(-/-) mice mimic a hypothyroid state of cardiac gene expression, with alterations in myosin heavy chain and troponin I isoforms. Our findings reveal the first mRNA targets of FXR1 in muscle and support translational repression as a novel mechanism for cardiac muscle development and function.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectFXR1en_US
dc.subjectHearten_US
dc.subjectMuscleen_US
dc.subjectRNAen_US
dc.subjectRNA-binding proteinen_US
dc.subjectTranslationen_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineCell Biology & Anatomyen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorGregorio, Carol Cen_US
dc.contributor.chairGregorio, Carol Cen_US
dc.contributor.committeememberKrieg, Paul Aen_US
dc.contributor.committeememberSimon, Alex Men_US
dc.contributor.committeememberElliott, David Aen_US
dc.contributor.committeememberGranzier, Henk Len_US
dc.identifier.proquest11424en_US
dc.identifier.oclc752261278en_US
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