DYNC1H1 mutation alters transport kinetics and ERK1/2-cFos signalling in a mouse model of distal spinal muscular atrophy

Garrett, Caroline A, Barri, Muruj, Kuta, Anna, Soura, Violetta, Deng, Wenhan, Fisher, Elizabeth M C, Schiavo, Giampietro and Hafezparast, Majid (2014) DYNC1H1 mutation alters transport kinetics and ERK1/2-cFos signalling in a mouse model of distal spinal muscular atrophy. Brain, 137 (7). pp. 1883-1893. ISSN 1460-2156

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Mutations in the gene encoding the heavy chain subunit (DYNC1H1) of cytoplasmic dynein cause spinal muscular atrophy with lower extremity predominance, Charcot-Marie-Tooth disease and intellectual disability. We used the legs at odd angles (Loa) (DYNC1H1(F580Y)) mouse model for spinal muscular atrophy with lower extremity predominance and a combination of live-cell imaging and biochemical assays to show that the velocity of dynein-dependent microtubule minus-end (towards the nucleus) movement of EGF and BDNF induced signalling endosomes is significantly reduced in Loa embryonic fibroblasts and motor neurons. At the same time, the number of the plus-end (towards the cell periphery) moving endosomes is increased in the mutant cells. As a result, the extracellular signal-regulated kinases (ERK) 1/2 activation and c-Fos expression are altered in both mutant cell types, but the motor neurons exhibit a strikingly abnormal ERK1/2 and c-Fos response to serum-starvation induced stress. These data highlight the cell-type specific ERK1/2 response as a possible contributory factor in the neuropathological nature of Dync1h1 mutations, despite generic aberrant kinetics in both cell types, providing an explanation for how mutations in the ubiquitously expressed DYNC1H1 cause neuron-specific disease.

Item Type: Article
Schools and Departments: School of Life Sciences > Neuroscience
Subjects: Q Science > QH Natural history > QH0301 Biology > QH0501 Life
Depositing User: Majid Hafezparast
Date Deposited: 02 Feb 2015 19:22
Last Modified: 07 Mar 2017 04:38
URI: http://srodev.sussex.ac.uk/id/eprint/50216

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Project NameSussex Project NumberFunderFunder Ref
Development of induced pluripotent stem (iPS) cells from mutant mouse models in order to reduce animal useG0167NC3RS-NAT CENT FOR REPLM, REFINM & REDUCTN OF ANIMS IN RESCHG0900789-91302
Value in People Award (VIP)RA61WELLCOME TRUST081431/Z/06/Z