RETROGRADE TRANSPORT · The role of Rab7 in axonal retrograde transport and human pathologies
FP7 — People (Marie Curie Actions)
- Duration
- 2011-02-01 → 2013-01-31
- EU contribution
- €173,241
- Participants
- 1
- Scheme
- MC-IEF
Lines connect the coordinator with its partners.
Results in brief
The role of Rab7 in axonal retrograde transport and human pathologies
Endocytosis and sorting of membrane receptors and transporters are crucial steps for the regulation of intracellular signalling events involved in cell growth, development differentiation and metabolism. Interestingly, the small GTPase Rab7, mutated in the severe neuropathy Charcot-Marie-Tooth 2b (CMT2b) plays a major role in the control of endocytic trafficking and lysosomal degradation of membrane receptors. Its assigned roles include the regulation of cargo progression from early to late endosomes and the fusion of late endosomes, autophagosomes and multivesicular bodies with the lysosome. In particular, Rab7 also controls the delivery of activated growth factor receptors to lysosomes and the turnover of membrane nutrient receptors. Despite the important roles of Rab7 in regulating crucial cellular processes and its implication in human diseases, animal models for the study of Rab7 are currently not available. A recent N-ethyl-N-nitrosourea (ENU) mutagenesis screen performed in mice identified a mouse strain containing a novel mutation in Rab7 (Rab7mt), affecting an aminoacid residues extremely conserved through evolution and likely to be required for the interaction of Rab7 with downstream effectors, as shown by in silico analysis. In an effort to characterise this mutant, we found that EGFR downregulation in response to EGF is altered in cells expressing Rab7mt as compared to wild type Rab7 (Rab7wt). We performed pull-down assays to assess the importance of this residue for the binding of Rab7 to its downstream effectors, an approach that generated crucial information for the elucidation of the molecular mechanisms controlled by Rab7. Olga Martins de Brito, olga.martinsdebrito@gmail.com
Data: CORDIS, © European Union
Project objective
Neurons are highly polarized cells that depend on anterograde and retrograde transport for survival, differentiation and maintenance of their morphology. Recently, impairment of axonal trafficking has been implicated as a causative agent in a number of human neurodegenerative disorders, such as Charcot-Marie-Tooth type 2B (CMT2B) neuropathy. CMT2B is characterized by the selective loss of motor and sensory neurons due to mutations in the small GTPase Rab7. Rab7 is a key component of the endocytic pathway in all eukaryotic cells and plays a major role in regulating long-range retrograde transport in motor neurons. However, we know very little about the cargoes and signalling components that enter this route, and how their transport is regulated. Furthermore, no animal model for the in vivo study of Rab7 is currently available. Therefore, the initial focus of my research project will be to generate novel mouse models, in which the activity of Rab7 is impaired. I will generate and characterise these mutant strains together with experts in the field, who kindly agreed to collaborate to this project. Furthermore, these mutant animals represent an invaluable tool to characterize the molecular and cellular role of Rab7 in axonal retrograde transport and its involvement in human neurodegeneration.
Original text from CORDIS.
Participants
- CANCER RESEARCH UK LBG · LONDONCoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union