Cells of the neuroectoderm choose to become neurons after receiving proper environmental cues, both stimulatory and inhibitory. Much is known about factors that induce neurogenesis, but inhibitory regulation of neurogenesis is poorly understood. Experiments in invertebrates reveal that signals transmitted through the Notch/lin 12/glp1 family of transmembrane proteins determine the fate of individual cells by inhibiting differentiation of certain cell fates. Preliminary experiments by the applicants and others indicate that signaling via vertebrate Notch and Delta homologous is central to the choice of a neural fate in higher animals. However, the details of how Notch-Delta signaling guides mammalian neurogenesis have so far remained elusive. The applicants propose to evaluate Notch signaling in mammalian neurogenesis in the P19 cell line where neurogenesis and myogenesis respond to Notch signals. Using the tools developed and tested in vitro, the applicants plan to study the role of Notch signals on developing cerebral cortex neurons and in olfactory neurons in vivo. They then propose to determine the intracellular mechanisms of Notch-ligand signal transduction using these model systems as biological assays.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS035566-02
Application #
2445866
Study Section
Neurology C Study Section (NEUC)
Program Officer
Leblanc, Gabrielle G
Project Start
1996-09-01
Project End
1999-06-30
Budget Start
1997-07-01
Budget End
1998-06-30
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Pharmacology
Type
Schools of Dentistry
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Berechid, Bridget E; Kitzmann, Magali; Foltz, Daniel R et al. (2002) Identification and characterization of presenilin-independent Notch signaling. J Biol Chem 277:8154-65
Foltz, Daniel R; Santiago, Michelle C; Berechid, Bridget E et al. (2002) Glycogen synthase kinase-3beta modulates notch signaling and stability. Curr Biol 12:1006-11
Foltz, D R; Nye, J S (2001) Hyperphosphorylation and association with RBP of the intracellular domain of Notch1. Biochem Biophys Res Commun 286:484-92
Presente, A; Andres, A; Nye, J S (2001) Requirement of Notch in adulthood for neurological function and longevity. Neuroreport 12:3321-5
Chambers, C B; Peng, Y; Nguyen, H et al. (2001) Spatiotemporal selectivity of response to Notch1 signals in mammalian forebrain precursors. Development 128:689-702
Gaiano, N; Nye, J S; Fishell, G (2000) Radial glial identity is promoted by Notch1 signaling in the murine forebrain. Neuron 26:395-404
Palacino, J J; Berechid, B E; Alexander, P et al. (2000) Regulation of amyloid precursor protein processing by presenilin 1 (PS1) and PS2 in PS1 knockout cells. J Biol Chem 275:215-22
Berechid, B E; Thinakaran, G; Wong, P C et al. (1999) Lack of requirement for presenilin1 in Notch1 signaling. Curr Biol 9:1493-6
Franklin, J L; Berechid, B E; Cutting, F B et al. (1999) Autonomous and non-autonomous regulation of mammalian neurite development by Notch1 and Delta1. Curr Biol 9:1448-57