Dystroglycan N-terminal domain enables LARGE1 to extend matriglycan on α-dystroglycan and prevents muscular dystrophy

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Dystroglycan (DG) requires extensive post-translational processing to function as a receptor for extracellular matrix proteins containing laminin-G-like (LG) domains. Matriglycan is an elongated polysaccharide of alternating xylose and glucuronic acid that is uniquely synthesized on α-dystroglycan (α-DG) by like-acetylglucosaminyltransferase-1 (LARGE1) and binds with high affinity to matrix proteins like laminin. Defects in the post-translational processing of α-DG that result in a shorter form of matriglycan reduce the size of α-DG and decrease laminin binding, leading to various forms of muscular dystrophy. However, little is known regarding mechanisms that generate full-length matriglycan on α-DG (~150-250 kDa). Here, we show that LARGE1 can only synthesize a short, non-elongated form of matriglycan in mouse skeletal muscle that lacks the DG N-terminus (α-DGN), resulting in a ~100-125 kDa α-DG. This smaller form of α-DG binds laminin and maintains specific force but does not prevent muscle pathophysiology, including reduced force induced by eccentric contractions and abnormalities in neuromuscular junctions. Collectively, our study demonstrates that α-DGN is required for LARGE1 to extend matriglycan to its full mature length on α-DG and thus prevent muscle pathophysiology.

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  1. eLife assessment

    The authors show that the amino terminus of dystroglycan is required for the production of full-length matriglycan, and in its absence, a shorter matriglycan is produced that is still capable of binding laminin. alpha-DGN deficient mice have abnormal neuromuscular synapses and reduced lengthening contraction-induced force. Overall, the well-controlled and convincing data mostly support the main conclusions, which will be of interest to scientists in membrane biology, muscle biology, and glycobiology.

  2. Reviewer #1 (Public Review):

    Dystroglycan, composed of subunits alpha- and beta, is one of the most important non-integrin cellular adhesion complexes, fundamental to establishing a connection between the extracellular matrix and the cytoskeleton in skeletal muscle and in a wide variety of tissues. For a protein that is produced through the ER-Golgi and then trafficked and targeted through exocytosis at the plasma membrane, unraveling the molecular aspects of every step underlining its maturation must be considered to be of utmost importance.

    The authors show how the lack of the N-terminal domain of alpha-dystroglycan (aDGN), achieved specifically in the skeletal muscle of model mice, is partially disrupting the decoration with sugars of the central "mucin-like" region of alpha-dystroglycan own central 'mucin like' region. Specifically, it would impact one of the most crucial steps in such a process, i.e. the LARGE1 directed synthesis of matriglycan, with deleterious consequences for dystroglycan function. This is an important work representing another step to drawing a full picture of dystroglycan maturation, with interesting implications for our understanding of dystroglycan biology and pathology.


    Arising in part from previous knowledge acquired on the dystroglycan domain organization, a role for the N-terminal of alpha-dystroglycan in the maturation of the full-length subunit could be envisaged. The authors have set a series of experiments whose overall outcome is not in contrast with the hypothesis made (i.e. that of a possible role played by aDGN in matriglycan elongation or modification).

    The presence of a link between the molecular structure of matriglycan and the genesis of muscular dystrophy has been further demonstrated.


    Some of the data, for example, those on the overexpressed aDGN, need to be re-assessed or re-interpreted providing more controls, if possible.

    More data should be reported on the histology and biochemistry of different types of muscle from a wider age range of mice. The degree and severeness of the observed muscular dystrophy phenotype remain a bit unclear. Especially, it should be better compared to the one observed in myd mice.

    The work does not show how the reaction mediated by LARGE (i.e. the synthesis of matriglycan) would ultimately take place through (or chaperoned by) aDGN, and no clarification is given on whether a direct interaction between aDGN and LARGE1 occurs.


    Overall, the results obtained seem to support the conclusions made about the importance of the N-terminal domain of alpha-dystroglycan for the elongation of matriglycan. I feel that there would be an "intrinsic elegance" in a mechanism in which an "internal quality, and length, control" is achieved by means of a protein subdomain belonging to the same protein that needs to be modified, which is processed away once its function is fulfilled. If the data could be further strengthened and opened to some alternative interpretations making the discussion more interesting and stronger, I think that this work can have a high impact in the field of dystroglycan biology and muscular dystrophy.

  3. Reviewer #2 (Public Review):

    Okuma, Hidehiko et al. investigated the role of dystroglycan N-terminus (alpha-DGN) in matriglycan synthesis and how the resultant shorter matriglycan affects muscle function and anatomy, and neuromuscular junction formation. Using transgenic mice with muscle-specific loss of alpha-DGN, and DAG1 KO mice exogenously expressing alpha-DGN-deficient DG, they found in both types of mice that less and a shorter form of matriglycan was made. The shorter matriglycan is capable of binding laminin. Additional analyses revealed that the alpha-DGN deficient mice have abnormal neuromuscular synapses and reduced lengthening contraction-induced force. Interestingly, exogenous expression of alpha-DGN or LARGE1 overexpression does not restore the full-length matriglycan or rescue the phenotypes. The authors also compared three transgenic mouse models with different matriglycan lengths and found correlations between matriglycan length and eccentric contraction force, centrally located nuclei (inverse correlation), and laminin binding. These data provide additional insights into the mechanisms underlying matriglycan synthesis and dystroglycanopathies.

    The main conclusion of this paper, which is that synthesis of full-length matriglycan requires alpha-DGN, is well supported by data. However, the lack of phenotypic rescue by exogenous alpha-DGN expression makes it difficult to draw a more generalized cause-and-effect conclusion between alpha-DGN, matriglycan length, and pathologies.