Journal article
LARGE glycans on dystroglycan function as a tunable matrix scaffold to prevent dystrophy
Nature (London), Vol.503(7474), pp.136-140
11/07/2013
DOI: 10.1038/nature12605
PMCID: PMC3891507
PMID: 24132234
Abstract
The dense glycan coat that surrounds every cell is essential for cellular
development and physiological function
1
, and it is becoming appreciated that its composition is
highly dynamic. Post-translational addition of the polysaccharide repeating unit
[-3-xylose-α1,3-glucuronic acid-β1-]
n
by like-acetylglucosaminyltransferase (LARGE) is required for the glycoprotein
dystroglycan to function as a receptor for proteins in the extracellular
matrix
2
,
3
. Reductions in the amount of
[-3-xylose-α1,3-glucuronic acid-β1-]
n
(hereafter referred to as LARGE-glycan) on dystroglycan result in heterogeneous
forms of muscular dystrophy
4
.
However, neither patient nor mouse studies has revealed a clear correlation
between glycosylation status and phenotype
5
,
6
. This disparity
can be attributed to our lack of knowledge of the cellular function of the
LARGE-glycan repeat. Here we show that coordinated upregulation of
Large
and dystroglycan in differentiating mouse muscle
facilitates rapid extension of LARGE-glycan repeat chains. Using synthesized
LARGE-glycan repeats we show a direct correlation between LARGE-glycan extension
and its binding capacity for extracellular matrix ligands. Blocking
Large
upregulation during muscle regeneration results in
the synthesis of dystroglycan with minimal LARGE-glycan repeats in association
with a less compact basement membrane, immature neuromuscular junctions and
dysfunctional muscle predisposed to dystrophy. This was consistent with the
finding that patients with increased clinical severity of disease have fewer
LARGE-glycan repeats. Our results reveal that the LARGE-glycan of dystroglycan
serves as a tunable extracellular matrix protein scaffold, the extension of
which is required for normal skeletal muscle function.
Details
- Title: Subtitle
- LARGE glycans on dystroglycan function as a tunable matrix scaffold to prevent dystrophy
- Creators
- Matthew M Goddeeris - Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USABiming Wu - Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USADavid Venzke - Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USATakako Yoshida-Moriguchi - Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USAFumiaki Saito - Department of Neurology and Neuroscience, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, JapanKiichiro Matsumura - Department of Neurology and Neuroscience, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, JapanSteven A Moore - Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USAKevin P Campbell - Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USA
- Resource Type
- Journal article
- Publication Details
- Nature (London), Vol.503(7474), pp.136-140
- DOI
- 10.1038/nature12605
- PMID
- 24132234
- PMCID
- PMC3891507
- NLM abbreviation
- Nature
- ISSN
- 0028-0836
- eISSN
- 1476-4687
- Grant note
- U54 NS053672 || NS / National Institute of Neurological Disorders and Stroke : NINDS
- Language
- English
- Date published
- 11/07/2013
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Pathology; Iowa Neuroscience Institute
- Record Identifier
- 9984013200802771
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