Related Experiment Video
Updated: Jun 3, 2026
Using Enzyme-based Biosensors to Measure Tonic and Phasic Glutamate in Alzheimer's Mouse Models
Published on: May 3, 2017
Enhanced neuronal Met signalling levels in ALS mice delay disease onset
M Genestine1, E Caricati, A Fico
1Developmental Biology Institute of Marseille-Luminy, UMR 6216, CNRS-Inserm-Université de la Méditerranée, Campus de Luminy-Case 907, Marseille Cedex 09, France.
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 Rosa26(LacZ-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.
Insights
Enhanced receptor tyrosine kinase (RTK) signaling, specifically Met, in motor neurons (MNs) did not impact development but improved outcomes in neurodegenerative disease models. This suggests RTKs can counteract toxic signals in conditions like amyotrophic lateral sclerosis (ALS).
Area of Science:
- Neuroscience
- Cellular Biology
- Molecular Biology
Background:
- Receptor tyrosine kinases (RTKs) regulate fundamental cellular processes.
- Aberrant RTK signaling is implicated in cancer and disease.
- RTKs are believed to counteract degenerative processes, prompting therapeutic exploration.
Purpose of the Study:
- To genetically investigate the role of enhanced Met receptor tyrosine kinase (RTK) signaling in neurons within a neurodegenerative disease context.
- To evaluate the biological and functional significance of Met RTK signaling in motor neuron (MN) development, maintenance, and disease progression.
Main Methods:
- Engineered conditional met-transgenic mice (Rosa26(LacZ-stop-Met)) for temporal and tissue-specific Met signaling enhancement.
- Assessed Met signaling effects on motor neuron development and maintenance.
- Introduced enhanced neuronal Met signaling into amyotrophic lateral sclerosis (ALS) mouse models.
Main Results:
- Increased neuronal Met levels did not affect motor neuron development or maintenance in healthy mice.
- Enhanced neuronal Met signaling in ALS mice significantly prolonged lifespan.
- Treatment delayed disease onset, retarded motor neuron loss, and improved motor performance in ALS mice.
Conclusions:
- Receptor tyrosine kinases (RTKs) possess properties to counteract toxic signals in neurodegenerative diseases like ALS.
- Targeting neuronal RTK signaling, specifically Met, demonstrates therapeutic potential in ALS.
- Genetically assessing neuron-targeted agents is crucial for evaluating ALS treatment efficacy.
