Nikon Young Scientist Award:
Centrosome and microtubule dynamics regulate the balance of stem cell self-renewal and differentiation
Germán Camargo Ortega
Swiss Federal Institute of Technology in Zurich (Switzerland), University of Munich & Helmholtz Zentrum Muenchen, (Germany)
Understanding the mechanisms regulating stem cell homeostasis and their fate commitment is fundamental for their efficient manipulation and future use in regenerative medicine. Here, I describe the role of the novel centrosomal protein Akna in regulating the balance between selfrenewal and differentiation in stem cells by promoting centrosomal microtubule organization, nucleation, and growth. Akna mainly localizes at subdistal appendages of the mother centriole where it is necessary and sufficient to confer microtubule-organizing activity via microtubule anchoring and to promote microtubule nucleation to the interphase centrosome. This is achieved through the interaction with specific subsets of centrosomal and microtubule-associated proteins as revealed by proximity-dependent Biotin Identification (BioID) and mass spectrometry. We show the importance of this process in the epithelial to mesenchymal transition (EMT)-like delamination of NSC subtypes thereby promoting cells to move towards the subventricular zone (SVZ) where transit-amplifying progenitors reside and remain there until Akna levels decrease again, concomitant with the loss of centrosomal MTOC activity in mature neurons. Together with a similar function in human cerebral organoids, this work demonstrates a novel mechanism regulating NSC maintenance versus differentiation, serving to expand the SVZ and numbers of transit-amplifying progenitors in ontogeny and phylogeny. Furthermore, beyond the developing brain, the role of Akna can have broader relevance, for example in adult neural progenitors, hematopoietic stem cells, but also in mammary epithelial cells undergoing EMT. In all cases, Akna levels are upregulated upon differentiation, and during EMT specifically, Akna is necessary for dissociation of junctional complexes. This, thus, highlights the importance of centrosomal microtubule organization in other contexts of development and cancer.