Control of the cell cycle and neurogenesis
The question we address is how proliferation, specification and neuronal differentiation are coordinated during the early phases of spinal cord development. The spinal cord develops in a head to tail sequence from the caudal neural plate. The FGF promotes the continuous development of that structure by maintaining a stem zone of proliferating neural precursors. Those escaping from that caudal stem zone are exposed to the Shh signal, which controls the proliferation and specification of ventral precursors. Soon after neural precursor cells will exit the cell cycle and initiate their differentiation. While the molecular mechanisms involved in the specification and differentiation have been largely studied those controlling proliferation and cell cycle exit remain enigmatic. In the last years, we showed that the level of the transcription factor Pax6 in neural progenitor cells is critical for their behaviour: a faint level of Pax6 is compatible with proliferation; increasing its level of expression selects the precursor for cell cycle exit but Pax6 needs to be switch off for the selected precursor to initiate its neuronal differentiation. In parallel we identified cell cycle regulators which are differentially expressed in the different phases of spinal cord maturation. We thus observed that the cyclin D2 and D1, positive regulators of G1 progression, are respectively controlled by FGF and Shh thus maintaining pools of proliferating neural precursors. We also identified an unexpected link between the phosphatase CDC25B, a regulator of the G2/M transition and the Shh pathway. Our aim is now: -to identify how the level of Pax6 affects neural progenitor behaviour particularly the putative links with the cell cycle machinery; to determine the importance of the Shh- dependant activation of CDC25B on neurogenesis during spinal cord development and in adult brain; to identify new genes involved in the process of spinal cord maturation by means of a global transcriptomic analysis.
PITUELLO Fabienne DR2, CNRS AGIUS Eric CR1, CNRS BEL-VIALAR Sophie CR1, CNRS MEDEVIELLE François AI, CNRS BONNET Frédéric PhD student MENRT fellowship HERMITTE stéphanie M2R student
Lacomme M, Liaubet L, Pituello F, Bel-Vialar S.: NEUROG2 drives cell cycle exit of neuronal precursors by specifically repressing a subset of cyclins acting at the G1 and S phases of the cell cycle.Mol Cell Biol. 2012 Jul;32(13):2596-607. Peco E, Escude T, Agius E, Sabado V, Medevielle F, Ducommun B, Pituello F.: The CDC25B phosphatase shortens the G2 phase of neural progenitors and promotes efficient neuron production.Development. 2012 Mar;139(6):1095-104. Douaud M, Feve K, Pituello F, (...)