May 3, 2019

Sergi Junyent Espinosa

14.00-14.15 Sergi Junyent Espinosa

‘tbc’

Stem cells (SCs) can respond to both self-renewal and differentiation signals in the niche, but the mechanisms behind signal detection, recognition and recruitment remain elusive. A fundamental signal in the niche is Wnt, a hydrophobic signalling ligand that is usually presented locally to receiving cells. To recapitulate early events in the cell-niche interaction and to study how stem cells recognise their niche, we covalently immobilised biologically active Wnt proteins to microbeads and presented them to a variety of Wnt responsive SCs, observing that SCs use cellular protrusions for their recruitment. Only naïve pluripotent SCs showed selective recruitment of the self-renewal signal Wnt3a. We show that the selectivity is mediated by Wnt3a interaction with the Wnt co-receptor Lrp6 and the interaction with members of the AMPA/Kainate family of glutamatergic receptors. Wnt ligand contact induces localized Ca2+ transients on the protrusion, allows local Wnt/β-catenin activation and facilitates Wnt recruitment. Wnt3a beads initiate a polarizing event that involves F-actin and β-catenin and leads to mitotic spindle orientation and asymmetric cell division. While Lrp6 control orientation precision, cell polarization and spindle orientation are mainly mediated by the co-receptor Lrp5. Asymmetric cell division is ensured by Lrp6 and the activation of the transcriptional Wnt/β-catenin pathway. Together, our data provides insight into the mechanisms that pluripotent SCs use to detect and react to self-renewal signals and presents molecular understanding of the contact-mediated signalling leading to oriented asymmetric cell division. Our results point to an unexplored partnership between Wnt and glutamatergic signalling in the SC niche.