The atypical Rac activator Dock180 (Dock1) regulates myoblast fusion in vivo

Abstract

Dock1(also known as Dock180) is a prototypical member of a new family of atypical Rho GTPase activators. Genetic studies in Drosophila and Caenorhabditis elegans have demonstrated that Dock1 orthologues in these organisms have a crucial role in activating Rac GTPase signaling. We generated mutant alleles of the closely related Dock1 and Dock5 genes to study their function in mammals. We report that while Dock5 is dispensable for normal mouse embryogenesis, Dock1 has an essential role in embryonic development. A dramatic reduction of all skeletal muscle tissues is observed in Dock1-null embryos. Mechanistically, this embryonic defect is attributed to a strong deficiency in myoblast fusion, which is detectable both in vitro and in vivo. Furthermore, we have uncovered a contribution of Dock5 toward myofiber development. These studies identify Dock1 and Dock5 as critical regulators of the fusion step during primary myogenesis in mammals and demonstrate that a specific component of the myoblast fusion machinery identified in Drosophila plays an evolutionarily conserved role in higher vertebrates. Dock5 ͉ mouse model ͉ myogenesis ͉ Myoblast City

The Rac1 exchange factor Dock5 is essential for bone resorption by osteoclasts

“…In line with this hypothesis, we reported previously that Dock1 and Dock5 are partially redundant during muscle fiber formation. (14) Consistent with the restricted distribution of Dock5, Dock5 -/-mice do not present major phenotypic defects. In particular, they are fertile and breed normally, whereas Dock5 is expressed in testis and placenta, suggesting that Dock5 may not play an essential role in these tissues.…”

“…1A). Purified antibodies directed against the C-terminal end of Dock5 (14) confirmed the great increase in Dock5 expression during osteoclastic differentiation of BMMs (Fig. 1B) and RAW264.7 cells (Fig.…”

“…(14) Mice used were 4 to 8 weeks old and were maintained at the animal facilities of the CNRS in Montpellier, France, and of the IRCM in Montreal, Quebec, Canada.…”

“…Through these domains, Dock1 interacts with CrkII, Crk-L, and ELMO proteins and promotes Rac1 activation for efficient actin remodeling, cell migration and adhesion, and myoblast and macrophage fusion. (12)(13)(14)(15) In a previous study we found that RANKL activates the transcription of Dock5. (16) In addition, Dock5 is among the membrane-associated proteins most significantly overexpressed in OCs as compared with macrophages.…”

FuRMAS: triggering myoblast fusion in Drosophila

“…In addition, Crk, Dock180 (Dock1, Mbc homolog) and Kette/NAP1/Hem are known to be expressed in C2C12 murine myoblast cells (Kesper et al, 2007). Importantly, Dock180 null mice have severely reduced levels of all skeletal muscle tissues due to a strong decrease in myoblast fusion events (Laurin et al, 2008). Taken together, these findings suggest that myoblast fusion might be controlled by a similar mechanism in vertebrates as found in Drosophila.…”