Notch-dependent regulation of neural stem cells in the neurovascular niche

• Applicant: Professor Dr. Mirko H.H. Schmidt
• Subject Area: Cognitive, Systems and Behavioural Neurobiology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2016 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 320929132

In the adult mammalian brain new neurons are created throughout its lifetime. One of the two major germinal niches is localized beneath the lateral walls of the lateral ventricles and is termed the subventricular zone (SVZ). Neural stem cells (NSCs) reside in the SVZ and give rise to transit amplifying precursors and neuroblasts, which depart from the SVZ and travel towards the olfactory bulb (OB). There, adult-born interneurons integrate into the local circuitry and contribute to olfactory information processing. The molecular mechanisms orchestrating these events rely heavily on Notch signaling as a central regulator of cell fate decision. However, little is known about the precise regulation of NSC differentiation and SVZ departure by Notch. Furthermore, the contribution of Notch to the integration of new neurons into the existing neural network in the OB has barely been elucidated. One significant regulator of the NSC lifecycle is the perivascular niche, which is formed by blood vessels surrounding NSCs. It provides a specialized basal lamina that supports stem cell identity and contributes to the mobilization of SVZ residents. Recently, we identified the epidermal growth factor-like protein 7 (EGFL7), a member of a larger group of EGF-like proteins (EGFLs), as a novel component of the extracellular matrix surrounding blood vessels (Blood, 2013). Previously, we had demonstrated that EGFL7 secreted by neurons and endothelial cells decreased the self-renewal potential of NSCs and stimulated neuronal differentiation of NSCs by the inhibition of Notch (Nat Cell Biol, 2009). Furthermore, EGFL7 was upregulated by blood vessels upon stroke (Acta Neuropathol, 2014). These findings offer EGFL7 as a novel component of the perivascular niche and a neurovascular regulator of NSCs.In our project, we will I) analyze how EGFL7 and other EGFLs regulate SVZ-derived NSCs in vivo by using intraventricular injections and knock-out models. Additionally, we will explore which components of the Notch pathway are involved in cell fate decision processes of NSCs. II) Subsequently, we will analyze how these proteins regulate neurogenesis in the OB and we will study the functionality of newly created neurons in vivo using our new mouse models in behavior paradigms. III) Lastly, we will compare the contributions of neural and vascular cells in the perivascular stem cell niche to the regulation of NSCs by the application of inducible tissue-specific knock-out and knock-in mouse models. Our project will yield a detailed understanding of the role of EGFLs and Notch in the regulation of NSCs and we will achieve a deeper understanding of the role of the neuro-vascular interface. Learning how blood vessels and NSCs communicate to regulate neurogenesis gives us the opportunity to manipulate the NSC pool by simple injection, which may provide an avenue for the exploitation of NSCs for therapeutic purposes, e.g., for the treatment of stroke and benefit for the patients.

• DFG Programme: Research Grants