Dynamic instability of microtubules requires dynamin 2 and is impaired in a Charcot-Marie-Tooth mutant

Abstract

Dynamin is a fission protein that participates in endocytic vesicle formation. Although dynamin was originally identified as a microtubule-binding protein, the physiological relevance of this function was unclear. Recently, mutations in the ubiquitously expressed dynamin 2 (dyn2) protein were found in patients with Charcot-Marie-Tooth (CMT) disease, which is an inherited peripheral neuropathy. In this study, we show that one of these mutations, 551Δ3, induces prominent decoration of microtubules with the mutant dyn2. Dyn2 was required for proper dynamic instability of microtubules, and this was impaired in cells expressing the 551Δ3 mutant, which showed a remarkable increase in microtubule acetylation, a marker of stable microtubules. Depletion of endogenous dyn2 with a small interfering RNA also resulted in the accumulation of stable microtubules. Furthermore, the formation of mature Golgi complexes, which depends on microtubule-dependent membrane transport, was impaired in both dyn2 knockdown cells and cells expressing the 551Δ3 mutant. Collectively, our results suggest that dyn2 regulates dynamic instability of microtubules, which is essential for organelle motility, and that this function may be impaired in CMT disease.

Dynamin 2 regulates biphasic insulin secretion and plasma glucose homeostasis

“…Dynamin may regulate actin function through both direct and indirect mechanisms in β cells. First, dynamin interacts with actin cytoskeleton through direct binding to F-actin (88) and microtubules (89) or through indirect interactions with actin-binding/regulatory molecules (90)(91)(92). For example, dynamin can directly bind actin filaments through a conserved actin-binding domain between amino acid 399 and 444, and the point mutation of this domain specifically decreases the dynamin-binding affinity to actin without affecting endocytosis (88).…”

Hypothesis review: are clathrin-mediated endocytosis and clathrin-dependent membrane and protein trafficking core pathophysiological processes in schizophrenia and bipolar disorder?

“…Rab7 mutations are responsible for Charcot-Marie-Tooth (CMT) type 2B neuropathy 129 . Interestingly, CMT is also associated with another protein with CME activity, Dynamin 2 130 . Rab 39B is believed to be involved in endosomal trafficking and to have roles in neurite arborisation and growth cone development 131 .…”

Cytoskeletal dynamics and spermatogenesis

“…One plausible mechanism is that the induction of MT catastrophe facilitates the release of signalling molecules transported to the MT plus end (Wu et al 2006;Efimov et al 2008), which in turn destabilize the junction. The requirement of dynamin in this process might be partly due to its role in regulating dynamic instability of MTs (Tanabe & Takei 2009). …”