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Miro dependent mitochondrial dynamics and the regulation of neuronal migration

Periodic Reporting for period 1 - MiroMigration (Miro dependent mitochondrial dynamics and the regulation of neuronal migration)

Reporting period: 2016-04-04 to 2018-04-03

Regulated trafficking of mitochondria is essential for providing ATP at the correct spatial location to power neural computation, and for providing Ca2+ buffering at sites of Ca2+ entry or release. In neurons, the concentration of mitochondria in specific regions such as growth cones and synapses is important for correct neuronal function and development. Consequently, defective mitochondrial trafficking is increasingly implicated in neurological diseases. Very little is known regarding the role of mitochondrial positioning and function during neural development such as during the migration of cortical neurons. The mature cerebral cortex is made up of cell layers with distinct neuronal subtypes formed by a series of well-controlled cell migration and specification events. In mature neurons, mitochondria move around synaptic regions where they generate energy in the form of ATP and modulate synaptic calcium (Ca2+) concentration, which are essential for proper synaptic function and plasticity. The important phases of cortical development include neurogenesis and differentiation; neuronal migration and morphogenesis (i.e. multipolar to bipolar shape, movement of the nucleus) and synaptogenesis. During neuronal migration, newborn neurons generated from progenitors in the ventricular zone (VZ), migrate along radial glial fibers to populate the cortical plate (CP). In migrating neurons, mitochondria accumulate at specific subcellular regions where there are high energy demands (such as the cone of the leading process) but very little is known regarding the mechanisms that regulate their positioning and function during neuronal migration.
The main objective was to make a major advancement in our understanding of the role of signalling- dependent positioning of mitochondria for the earliest stages of neuronal development that are key to determining correct neuronal connectivity. I have proposed to examine how the mitochondrial Rho GTPase (Miro) protein, acting as an essential adaptor for microtubule-dependent mitochondrial transport influences cortical neuronal migration. We aimed to characterise the impact of Miro deletion on the mitochondria positioning and functions in migrating neurons and also the consequence on the neuronal migration. We have identified a novel protein interaction impacting the neuronal migration and the mitochondrial trafficking.
We found that mitochondria don’t have an homogeneous distribution along the migrating neuron such as they are more present in the cone of the leading process. We also observed that in these neurons, the deletion of Miro1 increases this heterogeneity of mitochondria distribution. Mitochondria are accumulated close to the soma and less present in the leading process tip. We have then established that Miro1 deletion in newborn neurons impacts the neuronal migration. We investigated the consequences of Miro1 deletion for generation of new neurons. We observed that the number of neuronal progenitors (future radial glia and neurons) in the ventricular zone is significantly decreased and this zone is also thinner than in the control animals. In parallel, the number of cells staying in the proliferation stage is increased on Miro1 deletion. We focussed on studying the behaviour of Miro1 deleted neurons during the migration in the cortical plate and observed a significant delay. In another part of this project, we have identified novel Miro-dependent protein complexes that induces a decrease of mitochondria trafficking in vitro and a severe delay of the neuronal migration.
My work on the how mitochondrial dynamics contribute to the regulation of neuronal migration and early brain development is currently being written up for publication. While this work mainly comprises fundamental research, our results will add to the knowledge base that may in the longer term form the basis for the identification by the pharmaceutical and biotech sector of drugable targets in neuropsychiatric and neurological disorders.The project also gave me the opportunity to extend my scientific network, particularly with the European Neuroscience community, by attending national and international meetings courses, including the UCL Neurosciences Symposium (London, UK), Redbrain (Geneva, Switzerland), Cortical Development Conference (Chania, Greece), Divisional Postdoc Seminar (London, UK). During the MSCA I have also actively collaborated with other research groups, leading to 1 publication where I will be co-first author. The second one is with world experts in the novel interactor function in King’s College London. In UCL, I am also part of the Biosciences post doc committee, we organize seminars every month and some social events to help post docs from different departments of the division to collaborate and exchange knowledges on career development. As a public engagement activity, I have mentored 2 students in the In2Science program, which offers underprivileged students in their final years at high school in deprived areas the opportunity to work alongside practising scientists for a 2-week period, giving them an insight into scientific research and development. The aim of the schedule is to raise the participation of bright underprivileged young people into Science degrees at top Universities. Last year, my student and I won the prize of the best video. Finally, the project has enabled me increase my transferable research skills, including but not limited to: expanding my knowledge of major questions in the field of cortical development, further experience in communicating the outcomes of my research, building collaborations, managing a multi-factorial project. All together, this MCSA and these outstanding environments within UCL gave me excellent opportunities to develop as an independent research scientist.
Cortical development