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Novel Functions of SMN Complex Members and Their Implications in Spinal Muscular Atrophy

Walker, Michael Patrick
http://rave.ohiolink.edu/etdc/view?acc_num=case1238793216

Abstract Details

2009, Doctor of Philosophy, Case Western Reserve University, Genetics.
Spinal Muscular Atrophy (SMA) is one of the most widespread genetic disorders in children. Genetic research into the disorder has identified the survival motor neurons 1 (SMN1) gene as the causative agent. The gene product, SMN, is found in a multiprotein particle, the SMN complex, required for the biogenesis of essential splicing factors, the U snRNPs. While much is known about the function of SMN within this complex, other member’s roles remain enigmatic. Recent investigations in muscle and motoneurons also point to additional functions for the SMN complex outside of snRNP biogenesis. These revelations have lead to a debate on whether or not SMA results from faulty snRNP production or from perturbation of another function(s). Clearly, a better understanding into all the members of the SMN complex would lead to a clearer view of snRNP biology and SMA etiology. The goal of my thesis was to determine the function of a little known member of the SMN complex, Gemin4, and investigate the role of the SMN complex in muscle function. Surprisingly, by utilizing a cell biological approach I discovered a putative role for Gemin4 with regard to import of the entire SMN complex. Gemin4 contains a functional nuclear localization signal (NLS) and can drive other members of the complex into the nucleus. The creation of a Gemin4 gene-trap mouse revealed that Gemin4 is essential. Finally, by using biochemical and genetic techniques, I discovered a novel role of the SMN complex in muscle function that is separate from snRNP biogenesis. At the molecular level the SMN complex is part of the contractile apparatus of both skeletal and cardiac muscle. Importantly, known muscle regulators, the calpains, directly process the core member of the complex, SMN. Mouse models of SMA show defective muscle phenotypes at the molecular level that are indicative of a novel role of the SMN complex. Thus, I have identified a novel function for a member of the SMN complex, Gemin4, and shown that the SMN complex has a separate function in striated muscle. My research adds substantial knowledge to the study of SMN complex function and SMA biology.
A Gregory Matera, PhD (Advisor)
Hua Lou, PhD (Committee Chair)
Bruce Lamb, PhD (Committee Member)
Eckhard Jankowsky, PhD (Committee Member)
171 p.
Molecular Biology
SMN; Gemin4; SMN COMPLEX; snRNP; SMA; calpain; Z-disc

Recommended Citations

Citations

  • Walker, M. P. (2009). Novel Functions of SMN Complex Members and Their Implications in Spinal Muscular Atrophy [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1238793216

    APA Style (7th edition)

  • Walker, Michael. Novel Functions of SMN Complex Members and Their Implications in Spinal Muscular Atrophy. 2009. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1238793216.

    MLA Style (8th edition)

  • Walker, Michael. "Novel Functions of SMN Complex Members and Their Implications in Spinal Muscular Atrophy." Doctoral dissertation, Case Western Reserve University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=case1238793216

    Chicago Manual of Style (17th edition)

case1238793216
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© 2009, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.