From mechanosensing to nuclear response: revealing the role of actin regulators for B cell diversification

The actin cytoskeleton functions in the nucleus, however its nuclear function in hematopoietic cells is largely unexplored.

The Wiskott-Aldrich syndrome proteins (WASp) family coordinate receptor signalling to changes in the actin cytoskeleton.

B cells provide a unique possibility to investigate the role for WASp mediated actin regulation in the nucleus because of their diversification of the B cell receptor in germinal centers. This process relies on chromatin remodelling, gene transcription, and DNA repair over large distances.

We hypothesize that controlled WASp activity and actin regulation from B cell receptor signalling to the nucleus is required for B cell diversification to maintain genomic stability and B cell functionality.

We propose:Aim 1: To define how the actin cytoskeleton transmit cell surface receptor signaling to a nuclear response by mechanotransduction.Aim 2: To reveal the role of WASp-mediated actin polymerization for chromatin remodelling and transcription during B cell diversification.Aim 3: To define how dysregulated WASp and actin signalling leads to B cell transformation and to identify new targets for B cell lymphoma.Using rare patient samples and unique animal models combined with cutting edge genomic approaches and super-resolution imaging, we expect that our research program will reveal the nuclear function of actin regulators in hematopoietic cells and provide novel explanations and treatment strategies for immunodeficiency diseases.