Cytoplasmic dynein heavy chain: the servant of many masters

Abstract

Cytoplasmic dynein is the main retrograde motor in all eukaryotic cells. This complex comprises different subunits assembled on a cytoplasmic dynein heavy chain 1 (DYNC1H1) dimer. Cytoplasmic dynein is particularly important for neurons because it carries essential signals and organelles from distal sites to the cell body. In the past decade, several mouse models have helped to dissect the numerous functions of DYNC1H1. Additionally, several DYNC1H1 mutations have recently been found in human patients that give rise to a broad spectrum of developmental and midlife-onset disorders. Here, we discuss the effects of mutations of mouse and human DYNC1H1 and how these studies are giving us new insight into the many critical roles DYNC1H1 plays in the nervous system.

Keywords: Cramping 1; Legs at odd angles; Sprawling; amyotrophic lateral sclerosis; axonal transport; motor neurons; neurodegeneration.

Figure 1

The cytoplasmic dynein complex. (A) Diagram of the cytoplasmic dynein motor complex including the heavy chain (HC) dimer and its associated subunits. A model of the motor domain built from yeast cytoplasmic dynein (PDB ID 4AKG) and the mouse microtubule-binding domain (MTBD) (PDB ID 3ERR) assembled by Dr A.P. Carter has been overlapped with the schematic of the dynein HC in its apo or post-power stroke form . Adapted, with permission, from The Company of Biologists (J. Cell Sci. 126, 705–713; [4]). The electron micrograph of an isolated molecule of monomeric dynein from Chlamydomonas reinhardtii flagella in its pre-power stroke form is shown for comparison on the right. Adapted with permission from Macmillan Publishers (Nature 421, 715–718; [93]). Conformational changes driven by ATP hydrolysis in the motor domain, which alter the relative position of the stem and the tail/linker, are hypothesised to lead to the power stroke and progression on microtubules . The HCs (in dark violet) contain the six AAA ATPase domains (in red), the stalk region, which includes the MTBD (in dark yellow and yellow, respectively), the buttress (in orange), and the linker region. HCs are associated with light intermediate chains (LICs) (in green), intermediate chains (ICs) (in cyan), and light chains (LCs) (in light yellow). (B) Domain composition of the cytoplasmic dynein HC. In addition to the functional domains shown in (A), this scheme displays the homodimerisation region and linker (in white). The positions on the dynein HC of the three mouse mutations (Loa, Legs at odd angles; Cra, Cramping 1; Swl, Sprawling; bottom) and the human mutations discussed in this review (top) are indicated.

Figure 2

Quantitative analysis of axonal retrograde transport by intravital microscopy. (A) Axonal retrograde transport of signalling endosomes containing a fluorescently labelled atoxic fragment of tetanus neurotoxin was monitored in single axons in the intact sciatic nerve by time-lapse confocal microscopy and shown as a time series . (B) The deficit in axonal retrograde transport observed in early symptomatic SOD1^G93A transgenic mice (74 ± 1.7 days; in red) is almost completely rescued by the Dync1h1^Loa allele in Dync1h1^+/LoaSOD1^G93A double-mutant mice (in blue). The speed distribution profile displayed by Dync1h1^+/LoaSOD1^G93A mice overlaps with that observed in Dync1h1^+/Loa animals (in green) and is slightly shifted towards lower speed values compared with wild type mice (in black) of similar age.