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Cdc42 : polarization of the megakaryocyte and beyond

Frédérique Gaits-Lacovini, from INSERM Toulouse (Institut des maladies métaboliques et cardiovasculaires), will give a lecture about "Cdc42 : polarization of the megakaryocyte and beyond" at a seminar of Laboratory of Biology and Applied Pharmacology.
Ajouter à mon agenda 2024-03-26 04:47:44 2024-03-26 04:47:44 Cdc42 : polarization of the megakaryocyte and beyond Frédérique Gaits-Lacovini, from INSERM Toulouse (Institut des maladies métaboliques et cardiovasculaires), will give a lecture about "Cdc42 : polarization of the megakaryocyte and beyond" at a seminar of Laboratory of Biology and Applied Pharmacology. IDA Building, Chemla Auditorium ENS-PARIS-SACLAY webmaster@ens-paris-saclay.fr Europe/Paris public

Blood platelets are produced by large precursor cells, megakaryocytes (MKs), which extend cytoplasmic protrusions (proplatelets, PPTs) into bone marrow sinusoids. The molecular cues that control MKs polarization and limit transendothelial crossing to PPTs remain unknown.

We have investigated the impact of the actin cytoskeleton dynamics in differentiating MKs. We found that Cdc42 plays a crucial role in driving  polarized formation and structuration of the demarcation membrane system (DMS), a complex cytosolic reservoir of membranes for future platelets (1).

In parallel, we found that Cdc42 and RhoA act as a regulatory circuit downstream of the MK-specific mechanoreceptor GPIb. Cdc42 (go-signal) and RhoA (stop-signal) are at the centre of a molecular checkpoint that controls transendothelial platelet biogenesis (2).

Cdc42 and linear podosomes

Finally, we demonstrated that in those processes regulated by contacts with the extracellular matrix and cytokines, MKs form different types of podosomes. Contacts to collagen fibers initiated the formation of linear Factin structures enriched in cortactin that are reminiscent of linear podosomes. While classical punctae podosomes allow digestion of the bone marrow matrix and cellular crossing, linear podosomes appeared as points of contact between collagen fibers and the DMS, suggesting that they might be involved in protrusion elongation.

Interestingly, unlike other models, in MKs, only linear podosomes are regulated by Cdc42. Altogether, our findings put F-actin and its regulator Cdc42 at the fore front of platelets production, while it was previously thought that only Tubulin had any effect.