TERC3 - Tremplin-ERC

Development of the human neocortex: deciphering the molecular mechanisms of neural stem cell proliferation – HumanCortex.

Submission summary

Expansion of the neocortex during evolution has played a key role in the appearance of higher cognitive functions in humans. Neocortex development occurs via proliferation of neural stem cells that generate all neocortical neurons, and developmental defects can lead to severe cortical malformations. The central goal of this proposal is to unravel how human neural stem cells proliferate and self-renew to expand their pool and sustain the development of the greatly enlarged human neocortex.

In mice, the major neural stem cells are the apical Radial Glial (aRG) cells, which are highly elongated cells extending long apico-basal cytoplasmic processes. The remarkable expansion of the human neocortex is thought to arise from an additional pool of neural stem cells, the basal Radial Glial (bRG) cells. Because of their extreme rarity in rodent models, the mechanisms controlling proliferation and self-renewal of bRG cells remain largely unexplored. Combining microfluidics, generation of cerebral organoids, culture of human fetal brain slices and state-of-the-art live imaging techniques we will:

Aim1: Examine how the dynein molecular motor enables expansion of the human bRG cell pool. Mutations in dynein and dynein-associated factors are highly associated with human cortical malformations. We hypothesise that dynein controls critical aspects of human bRG cell behavior, including cell migration, mitotic spindle positioning and proliferation.

Aim2: Identify polarised cell fate regulators in mouse and human aRG and bRG cells.
The fate of RG cells and their ability to self-renew has been tightly associated with the maintenance of their basal process. We hypothesise that critical cell fate regulators are asymmetrically localised to this cytoplasmic process.

With this project we will identify key molecular mechanisms controlling human neurogenesis, which is fundamental to understand cerebral malformations such as genetically or pathogen-induced microcephaly.

Project coordination

Alexandre Baffet (INSTITUT CURIE - SECT DE RECHERCHE)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

IC INSTITUT CURIE - SECT DE RECHERCHE

Help of the ANR 150,000 euros
Beginning and duration of the scientific project: December 2017 - 18 Months

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