Enhanced neuronal Met signalling levels in ALS mice delay disease onset
Open Access
- 17 March 2011
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Disease
- Vol. 2 (3), e130
- https://doi.org/10.1038/cddis.2011.11
Abstract
Signalling by receptor tyrosine kinases (RTKs) coordinates basic cellular processes during development and in adulthood. Whereas aberrant RTK signalling can lead to cancer, reactivation of RTKs is often found following stress or cell damage. This has led to the common belief that RTKs can counteract degenerative processes and so strategies to exploit them for therapy have been extensively explored. An understanding of how RTK stimuli act at cellular levels is needed, however, to evaluate their mechanism of therapeutic action. In this study, we genetically explored the biological and functional significance of enhanced signalling by the Met RTK in neurons, in the context of a neurodegenerative disease. Conditional met-transgenic mice, namely Rosa26LacZ−stop−Met, have been engineered to trigger increased Met signalling in a temporal and tissue-specific regulated manner. Enhancing Met levels in neurons does not affect either motor neuron (MN) development or maintenance. In contrast, increased neuronal Met in amyotrophic lateral sclerosis (ALS) mice prolongs life span, retards MN loss, and ameliorates motor performance, by selectively delaying disease onset. Thus, our studies highlight the properties of RTKs to counteract toxic signals in a disease characterized by dysfunction of multiple cell types by acting in MNs. Moreover, they emphasize the relevance of genetically assessing the effectiveness of agents targeting neurons during ALS evolution.Keywords
This publication has 42 references indexed in Scilit:
- Abl interconnects oncogenic Met and p53 core pathways in cancer cellsCell Death & Differentiation, 2011
- IFNγ triggers a LIGHT-dependent selective death of motoneurons contributing to the non-cell-autonomous effects of mutant SOD1Cell Death & Differentiation, 2010
- Cell Signaling by Receptor Tyrosine KinasesCell, 2010
- Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosisNature Neuroscience, 2008
- Hepatocyte growth factor promotes endogenous repair and functional recovery after spinal cord injuryJournal of Neuroscience Research, 2007
- c-Met is essential for wound healing in the skinThe Journal of cell biology, 2007
- Combined Signaling through ERK, PI3K/AKT, and RAC1/p38 Is Required for Met-triggered Cortical Neuron MigrationPublished by Elsevier BV ,2006
- Virus‐delivered small RNA silencing sustains strength in amyotrophic lateral sclerosisAnnals of Neurology, 2005
- Mouse limb deformity mutations disrupt a global control region within the large regulatory landscape required for Gremlin expressionGenes & Development, 2004
- Coupling Met to Specific Pathways Results in Distinct Developmental OutcomesMolecular Cell, 2001