Proprioceptive Sensory Neuropathy in Mice with a Mutation in the Cytoplasmic Dynein Heavy Chain 1 Gene

Abstract

Mice heterozygous for the radiation-induced Sprawling (Swl) mutation display an early-onset sensory neuropathy with muscle spindle deficiency. The lack of an H reflex despite normal motor nerve function in the hindlimbs of these mutants strongly suggests defective proprioception. Immunohistochemical analyses reveal that proprioceptive sensory neurons are severely compromised in the lumbar dorsal root ganglia of newborn Swl/ϩ mice, whereas motor neuron numbers remain unaltered even in aged animals. We have used positional cloning to identify a nine base-pair deletion in the cytoplasmic dynein heavy chain 1 gene (Dync1h1) in this mutant. Furthermore, we demonstrate that Loa/ϩ mice, which have previously been shown to carry a missense point mutation in Dync1h1 that results in late-onset motor neuron loss, also present with a severe, early-onset proprioceptive sensory neuropathy. Interestingly, in contrast to the Loa mutation, the Swl mutation does not delay disease progression in a motor neuron disease mouse model overexpressing a human mutant superoxide dismutase (SOD1 G93A ) transgene. Together, we provide in vivo evidence that distinct mutations in cytoplasmic dynein can either result in a pure sensory neuropathy or in a sensory neuropathy with motor neuron involvement.

Axon Transport and Neuropathy

“…63,64 Accordingly, heterozygous mice with an orthologous pathogenic mutation of DYNC1H1 have a marked reduction in dynein microtubule binding affinity and abnormal retrograde axon transport which produces a CMT-like motor and sensory neuropathy. 65,66 In addition, DYN-interacting proteins that function as cofactors or modulators of DYN function are identified to cause neuropathy. For example dynactin, which is a large heteromeric protein complex that interacts with DYN to modulate motor protein binding to cargo organelles for transport, contains a 150-kDa protein (the largest in the complex) that is encoded by the dynactin-1 gene (DCTN1; OMIM no.…”

From the Cell Membrane to the Nucleus: Unearthing Transport Mechanisms for Dynein

“…We could also account for the effects of multiple motors attaching to the cargo. However, the main goal of future research would be to adapt our model to take into account mutations in cytoplasmic dynein such as those found to cause Charcot-Marie-Tooth disease and spinal muscular atrophy in humans and neurodegeneration in mouse models [8,14,19,51].…”

“…The step size is usually 8 nm, although it has also been found to take the values of 16, 24 and 32 nm [36,40]. Mutations in the tail region of the cytoplasmic dynein causing Charcot-Marie-Tooth disease, intellectual disability [52] and spinal muscular dystrophy [20] in humans and neurodegeneration in mouse models have been described [8,14,19,51]. These mutations are likely to compromise the structure and the assembly of cytoplasmic dynein complex.…”

Mouse Forward Genetics in the Study of the Peripheral Nervous System and Human Peripheral Neuropathy

“…Tbce, which encodes a tubulin cofactor necessary for proper microtubule assembly, results specifically in motoneuron degeneration and apoptosis when mutated [35]. Mutations in Dync1h1, the dynein heavy chain 1 gene, affect retrograde transport and lead to sensory and/or motor neuron disease, depending on the allele [36,37]. Finally, the dysfunction of two endosome-associated genes, Fig4 and Vps54, causes neuropathy in mouse models.…”

“…The mapping of Swl to Dync1h1 led to a fresh examination of the Loa phenotype and similar early-onset sensory deficits were discovered. Nevertheless, the three alleles do not share all phenotypic characteristics; the Swl mutation does not result in progressive motor neuron loss, nor can it delay the progression of the amyotrophic lateral sclerosis-like phenotype of the human superoxide dismutase transgenic model SOD G93A , as has been shown for Loa and Cra1 [36]. Therefore, comparison of Swl with Loa and Cra1 may also yield information on the tissuespecific importance of Dync1h1 retrograde transport.…”