The mechanisms regulating cell fate specification in the mammalian brain remain only partially understood. The Notch signaling pathway is known to regulate neural stem cells, although the function of Notch signaling in distinct proliferative neural subtypes remains unclear. Our recent findings have created a new foundation on which to investigate the regulation of neural progenitor heterogeneity, in particular with respect to Notch signaling. We have identified two molecularly distinct proliferative cell types in the neocortical ventricular zone (VZ), referred to hereafter as neural stem cells (NSCs) and intermediate neural progenitors (INPs). NSCs and INPs differentially utilize the Notch pathway, with the former signaling robustly through the canonical CBF1/Hes cascade, and the later possessing a stable attenuation and/or redirection of that cascade. The proposed studies will continue this novel line of investigation, with an emphasis on probing the differential regulation of Notch signaling in NSCs and INPs. In addition, as a new and exciting component of this work, we will examine a recently identified Notch pathway modulator, Pokemon (LRF/Zbtb7a), which has been shown to regulate Notch signaling in the immune system, and is expressed in the VZ of the developing brain. The proposed studies will employ a wide range of experimental approaches, including in vivo gain-of-function and loss-of-function, flow cytometry, chromatin immuno-precipitation (ChiP), and in vitro progenitor culturing and differentiation. These studies will greatly enhance our understanding of mammalian forebrain development. In addition, this work will contribute to the treatment of nervous system disorders, including brain cancer and neurodegenerative diseases, and to the treatment of traumatic brain injury.
These studies are designed to make important discoveries regarding neural stem cell regulation during mammalian brain development. The proposed work is based upon our recent novel findings that the Notch pathway is differentially utilized in neural stem and progenitor cells during neocortical development. We will examine the molecular basis of that differential signaling, and will determine the lineage relationship between neocortical neural stem and progenitor cells. We will also investigate the role of the Notch pathway regulator Zbtb7a (Pokemon/LRF), which we have found can negatively regulate Notch signaling in the embryonic neocortex. These studies will greatly enhance our understanding of mammalian forebrain development. In addition, this work may contribute to the treatment of nervous system disorders, including brain cancer and neurodegenerative diseases, and to the treatment of traumatic brain injury.
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