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Neural stem cells: a finely controlled destiny

The differentiation of the neural stem cell in glial cell is dependent on both Gcm and Repo protein levels, which jointly act in a first rising phase. Once Repo reaches a threshold value, it acts by inhibiting Gcm, causing a drastic drop of the protein level in the cell and the finalization of the glial cell differentiation.

Interlocked loops trigger lineage specification and stable fates in the Drosophila nervous system.

Flici H(1), Cattenoz PB(2), Komonyi O(3), Laneve P(2), Erkosar B(2), Karatas OF(2), Reichert H(4), Berzsenyi S(2), Giangrande A(3).

Nat Commun July 28, 2014

July 28, 2014

How is the formation of brain cells controlled ? The team of Angela Giangrande has just highlighted the molecular mechanisms of the fate of neural stem cells, at the origin of all cells constituting our brain. Their results are published on the 28th of July in the journal Nature communications.

The brain and its development
During the development of an organism, very plastic cells, called stem cells, differentiate into multiple specialized cells, thus allowing the smooth setting-up, structured in time and space, of different organs. Angela Giangrande’s team is specialized in the complex formation of the brain, and uses Drosophila as a model organism. In addition to nerve cells, the brain is composed of glial cells (or glia) forming the environment of neurons. Neurons and glia derive from the same neural stem cells (NSC) and the number and proportion of each cell type are fully controlled, hence guaranteeing the proper functioning of the brain.


Understanding the differentiation mechanisms of neural stem cells
The researchers focused on the mechanisms that enable NSC to differentiate into neurons or glia. In this new study, they demonstrated a sophisticated control system dependent on three proteins : the CBP acetylase Gcm (Glial cell missing), the master factor of gliogenesis and its target Repo (Reversed polarity). Levels of the latter two proteins act together to initiate glial cell differentiation. Repo feeds back positively onto Gcm expression and rapidly becomes self-sustained in an upward phase, before reaching a critical threshold. Beyond this level, Repo starts degrading Gcm via CBP, hence triggering the final stage and allowing the cell to complete its destiny of glia. When this ‘ménage à trois’ is deregulated, the number and proportion of glial cells are affected, leading to the death of the embryo.


The fate of cancer cells
The researchers also highlighted the presence of cells that are blocked in an ambiguous state half-neuron/half-glia, upon dysfunction of the regulatory loops. Such metastable state is similar to that observed in metastasis. This suggests that a dysfunction in the mechanisms triggering cell differentiation could cause a blockage of the cell in an intermediate vague state, and cause tumor development.


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