Periodicity in Netrin-1 signalling activity during the cell cycle controls stem cell features – PerioNet

The integration of multiple signals dictates the emergence and properties of pluripotent stem cells (PSC) during mammalian development. Understanding the balance between self-renewal and differentiation in PSC is highly relevant for developmental and reproductive biology but also for regenerative medicine. One of the most intriguing aspects of PSC biology is their capacity to respond to exogenous signals in a non-uniform manner. Among other processes, the cell cycle was found to contribute to such cell-to-cell variations in the response to differentiation signals. In detail, PSCs were found to respond more efficiently to differentiation when instructive signals are received during the G1 phase. However, the molecular determinants, and in particular the signalling pathways, that control cell cycle-regulated gene programs, and their impact on stem cell properties, are still largely unknown.
Partner#1 (P1) is pioneer in demonstrating that the Netrin-1 ligand and its cognate receptors Neo1 and Unc5b promote naïve pluripotency. Netrin-1 is a laminin-like secreted protein that has pleiotropic functions in development and cancer. The consortium, with experts in Netrin-1/stem cells (P1), cell cycle (P2) and protein dynamics/trafficking (P3), demonstrated unexpectedly that Netrin-1 signalling activity is periodic in PSCs. Netrin-1, Neo1 and Unc5b (NNU) expression is tightly coupled and specifically downregulated in G1. Therefore, the main hypothesis of PERIONET is that periodicity in NNU activity controls stem cell properties during the cell cycle. Using both rodent and human PSCs, PERIONET will (i) dissect the molecular mechanisms triggering the periodic regulation of NNU (Aim#1), (ii) investigate the function of such a periodicity on PSCs properties (Aim#2-3), and identify the molecular cascades and effectors of NNU in stem cells (Aim#4).