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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS046731-06A1
Application #
7790446
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Owens, David F
Project Start
2003-07-01
Project End
2011-08-31
Budget Start
2009-09-30
Budget End
2010-08-31
Support Year
6
Fiscal Year
2009
Total Cost
$442,938
Indirect Cost
Name
Johns Hopkins University
Department
Neurology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Liu, Shuxi; Wang, Yue; Worley, Paul F et al. (2015) The canonical Notch pathway effector RBP-J regulates neuronal plasticity and expression of GABA transporters in hippocampal networks. Hippocampus 25:670-8
Pierfelice, Tarran J; Schreck, Karisa C; Dang, Louis et al. (2011) Notch3 activation promotes invasive glioma formation in a tissue site-specific manner. Cancer Res 71:1115-25
Ever, Leah; Zhao, Rui-Jing; Eswarakumar, Veraragavan P et al. (2008) Fibroblast growth factor receptor 2 plays an essential role in telencephalic progenitors. Dev Neurosci 30:306-18
Dang, Louis; Yoon, Keejung; Wang, Mike et al. (2006) Notch3 signaling promotes radial glial/progenitor character in the mammalian telencephalon. Dev Neurosci 28:58-69