Thorsteinsdottir, S. | bioRxiv Science

bioRxiv2024

Deregulation of multiple mechanisms shapes the onset of LAMA2-congenital muscular dystrophy

LAMA2-congenital muscular dystrophy (LAMA2-CMD) is the most common congenital muscular dystrophy. This often-lethal disease is triggered by mutations in LAMA2, coding for laminin-2 chain, a key extracellular matrix (ECM) component, prevalent in the skeletal muscle. Several phenotypes have been associated with LAMA2-CMD, however, it is not yet known what mechanisms are faulty, right at disease onset in utero. Using the dyW mouse model of LAMA2-CMD we showed that the disease onset is characterized by a profound downregulation of gene expression, with a marked effect on cytoskeletal organization, myoblast differentiation and fusion and altered DNA repair and oxidative stress responses. Concordantly, we found that Lama2-deficient myoblast cells displayed proliferation and differentiation defects, increased oxidative stress and DNA damage. Together, our findings provide unique insights into the processes dependent on laminin-2 chain during muscle development, revealing its critical importance to maintain muscle cell homeostasis already at fetal stages.

developmental biology↗

bioRxiv2019

A fibronectin mechanotransduction pathway translates segmentation clock oscillations into periodic somite formation

Somitogenesis starts with cyclic waves of expression of segmentation clock genes in the presomitic mesoderm (PSM) and culminates with periodic budding of somites in its anterior-most region. How cyclic clock gene expression is translated into timely morphological somite formation has remained unclear. A posterior to anterior gradient of increasing PSM tissue cohesion correlates with increasing fibronectin matrix complexity around the PSM, suggesting that fibronectin-dependent tissue mechanics may be involved in this transition. Here we address whether the mechanical properties of the PSM tissue play a role in regulating the pathway leading to cleft formation in the anterior PSM. We first interfered with cytoskeletal contractility in the chick PSM by disrupting actomyosin-mediated contractility directly or via Rho-associated protein kinase function. Then we perturbed fibronectin matrix accumulation around the PSM tissue by blocking integrin-fibronectin binding or fibronectin matrix assembly. All four treatments perturbed hairy1 and meso1 expression dynamics and resulted in defective somitic clefts. A model is presented where a gradient of fibronectin-dependent tissue mechanics participates in the PSM wavefront of maturation by ensuring the correct spatio-temporal conversion of cyclic segmentation clock gene expression into periodic somite formation.

developmental biology↗