Neural stem cells of the adult rodent ventricular-subventricular zone: self-renewal of B1 cells and interactions of their subcellular domains with the niche

• Applicant: Kirsten Obernier, Ph.D.
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2011 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 201064443

Neural stem cells (NSCs, B1 cells) in the adult rodent ventricular-subventricular zone (V-SVZ) generate thousands of young neurons destined for the olfactory bulb every day. B1 cells have a remarkable morphology consisting of at least three subcellular domains that make specific contacts with their niche: I. apical: B1 cells contact the CSF of the lateral ventricles with a small apical surface that contains a single primary cilium and is surrounded by ependymal cells in a pinwheel-like structure; II. intermediate: B1 cells cell body with lateral processes is in intimate contact with their progeny (C and A cells) and possible intercellular feedback mechanism might control the tight balance between NSC proliferation and differentiation; III. basal: with a long basal end foot B1 cells contact blood vessels. It remains unclear how these subcellular domains and their interaction with their environment affects NSC behavior, their mode of division and lineage progression. Moreover, one cardinal property of stem cells - self-renewal - has not been directly demonstrated for B1 cells. Here I propose to investigate whether B1 cells can self-renew and how their domains might control their behavior. The project is aimed to directly observe neurogenesis by live-imaging and to investigate possible intercellular regulations of V-SVZ cell lineage progression. Preliminary data using time-lapse microscopy of ex vivo whole mount preparations reveal for the first time the dynamic interactions of B1 cells and their niche. B1 cells have lateral processes that frequently touch C cells (possibly their own progeny). The basal process is very dynamic; shifting position on the surface of the blood vessels and between neighboring vessels and also makes transitory contacts with other B1 cells. These previously unknown B1-B1 contacts appear to be correlated with B1 cells divisions. During cell division B1 cells maintain their unique morphology and remain in contact with blood vessels. Finally, these movies indicate self-renewing symmetric and asymmetric divisions of B1 cells. NSC division might be regulated by feedback mechanism between B1 cells and neighboring cells, for example via Notch signaling. Interestingly, short-term infusion of epidermal growth factor into the lateral ventricle induces overproliferation of C cells that is paralleled by increased apical contacts of B1 cells without affecting their proliferation. Preliminary data suggest that the increased proliferation of C cells is only transient and Notch signaling seems to be upregulated, whereas the number of proliferating B1 cells increases after restoration of C cell proliferation. This suggests a feedback mechanism between C and B1 cells controlling stem cell proliferation. Importantly, the additional B1 cells contacting the ventricle contribute to olfactory bulb neurogenesis.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Arturo Alvarez-Buylla, Ph.D.