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Elucidating the Molecular Mechanism of Myoblast Fusion in Vertebrates

projects.project_description

Entschlüsselung der Zellfusion in Muskeln

Die Skelettmuskulatur besteht aus funktionellen kontraktilen Einheiten, den sogenannten Muskelfasern, die durch die Fusion von Muskelzellen (Myoblasten) entstehen. Die Bildung von Muskelfasern setzt die Umformung und Fusion von Plasmamembranen voraus. Diese Prozesse sind jedoch noch nicht vollständig charakterisiert. Um diese Wissenslücke zu schließen, entwickelt das EU-finanzierte Projekt MYOCLEM licht- und elektronenmikroskopische 3D-Methoden und untersucht damit die beteiligten molekularen Faktoren sowie ihren Einfluss auf die Veränderungen, die während der Fusion bei der Membranumformung auftreten. Neue Erkenntnisse über den Mechanismus und die Regulierung der Fusion werden nicht nur zu einem besseren Verständnis dieses wichtigen Vorgangs beitragen, sondern auch die Entwicklung neuer Behandlungsformen gegen Muskelerkrankungen unterstützen.

projects.objective

Cell-to-cell fusion is a ubiquitous phenomenon essential for the physiological function of numerous tissues. A striking example is the fusion of myoblasts to form multinucleated myofibers during skeletal muscle development and regeneration. During myoblast fusion, membrane architecture must be radically remodeled. Yet, how membrane remodeling occurs on the molecular level is poorly understood as, until now, there was no approach available for visualizing dynamic changes in the cellular ultrastructure and the organization of the fusion machinery in situ.
To fill this gap, we have developed correlative light and 3D electron microscopy (CLEM) methods that allow us to identify fluorescent signals within EM samples with high sensitivity and subsequently localize the source of these signals with high precision. In this proposal, we will apply these methods in combination with live-cell imaging, biochemistry and cryo-electron tomography (ET) to deliver fundamental knowledge about the mechanism of myoblast fusion. Our specific aims are:
Aim 1: To resolve the molecular and ultrastructural events underlying cell fusion, by revealing how plasma membrane architecture is remodeled at sites of fusion using 3D EM.
Aim 2: To dissect the mechanism driving membrane remodeling during fusion, by visualizing how the fusion machinery assembles at sites of fusion and how its assembly is mirrored by changes in membrane shape, using biochemistry and live-cell imaging.
Aim 3: To determine the structure of the fusion machinery in situ, by using cryo-ET and subtomogram averaging.
Our synergetic experimental strategy will generate a quantitative, dynamic high-resolution view of the fusogenic synapse of vertebrate muscle, revealing how the fusion machinery remodels the plasma membrane at sites of fusion. These data are vital for deriving a biophysical model of myoblast fusion, understanding the general mechanism of cell fusion, and developing strategies to treat primary muscle diseases.

projects.funding_scheme

ERC-STG - Starting Grant
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projects.coordinator

WEIZMANN INSTITUTE OF SCIENCE
project_info.net_contribution
€ 1 500 000,00
projects.address
Herzl street 234
7610001 Rehovot
Israel

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projects.activity_type
Higher or Secondary Education Establishments
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project_info.non_eu_contribution
€ 0,00

projects.beneficiaries (1)