Characterization of C. Elegans Pat-9 and Frg-1, Genes Critical for Body Wall Muscle Development

For the FSHD project, a C. elegans homolog of the FSHD candidate gene FRG1 (FSHD region gene 1), ZK1010.3, was identified, cloned, renamed frg-1, and characterized. Surprisingly, both the endogenous and overexpressed FRG-1 was localized to the nucleus and the cytoplasm, contrary to what had been reported in the literature for human FRG1. Interestingly, in adult body wall muscle, FRG-1 associated with the cytoplasmic dense bodies whose primary function in C. elegans is to transfer mechanical force from muscle contraction to the cuticle by attaching the muscle fiber to the muscle cell membrane and the surrounding extracellular matrix (ECM). Thus, dense bodies are functionally similar to the vertebrate Z-disk and contain homologs of many of the same Z-disk proteins. Many other types of muscular dystrophy, such as Duchenne, Becker, certain limb-girdle dystrophies and some rare congenital muscular dystrophies result from mutations affecting vertebrate orthologs of dense body components. To date, our study of FRG-1 in C. elegans renders FRG-1 the only FSHD candidate gene with a direct link to muscle structure. In addition, overexpression of FRG-1 affects its distribution between the nucleus and cytoplasm, and 25% of transgenic animals overexpressing FRG-1 showed disruptions in body wall musculature, including smaller, misaligned, missing and disconnected muscle cells. FRG-1 is highly evolutionarily conserved suggesting human FRG1 may have the similar expression and function. This data strongly supports a role for mis-expressed FRG1 in mediating the disruption of muscle cell membrane integrity and muscle weakness in FSHD patients.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Cell and Developmental Biology

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2015

Author dc:creator

• Liu, Qian

Contributors dc:contributor

• Peter L. Jones

• Biology, Genetics

Language dc:language

eng

Identifier

(MiAaPQ)AAI3452235

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/86329