Cell-autonomous Jagged1 signaling as a mediator of neural stem cell differentiation
Final Report Abstract
During the course of this project, we were able to show that Jag1 transmits a cell autonomous signal to the cells that present it. Jag1 is cleaved in the extracellular and juxtamembrane domain in a regulated fashion by ADAM (beta-) and gamma-secretases. The released Jag1ICD translocates to the nucleus and binds chromatin. We performed yeast-2-hybrid and double mass-spectroscopic analysis of Jag1ICD interacting proteins. We found that PICK1 and PKCα[formula] bind the intracellular domain fo Jag1. Through biochemical and transgenic analysis, we showed that PICK1 and PKCα regulate proteolytic activation of the Notch ligand Jag1 to release its intracellular domain. Nuclear translocated Jag1ICD binds TBLR1 and core histones regulating Notch and Wnt/beta-Catenin target transcription. Jag1 mutant mice show persistence of neural progenitors and an aberrant onset of differentiation while Jag1ICD or PICK1 expression induces neurogenesis in vivo. Based on the results of this project, we propose that Jag1 is a signal integrator to modulate neural progenitor fate and drive the onset of differentiation in the developing brain.
Publications
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(2010). Quiescent and active hippocampal neural stem cells with distinct morphologies respond selectively to physiological and pathological stimuli and aging. Cell Stem Cell, 6:445-456
Lugert, S., Basak, O., Knuckles, P., Häussler, U., Haas, C., Fabel, K., Goetz, M., Kempermann, G., Giachino. C. and Taylor, V.
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(2010). RBPJk-dependent signalling is essential for long term maintenance of neural stem cells in the adult hippocampus. J Neurosci. 30:13794- 13807
Ehm, O., Göritz, C., Covic, M., Schwarz, T.J., Karaca, E., Kempkes, B., Kremmer, E., Schäffner, I., Pfrieger, F.W., Espinosa, L., Bigas, A., Giachino, C., Taylor, V., Frisén, J., and Lie, D.C.
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(2011). PNS progenitors can be reprogrammed to produce myelinating oligodendrocytes and repair brain lesions. J Neurosci. 31, 6379- 6391
Binder, E., Rukavina, M., Hassani, H., Nakatani, H., Weber, M., Parras, C., Taylor, V. and Rohrer, H.
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(2012). Homeostatic neurogenesis in the adult hippocampus does not involve amplification of Ascl1high intermediate progenitors. Nature Communications 3, 670
Lugert, S., Vogt, M., Tchorz, J.S., Müller, M., Giachino. C. and Taylor, V.
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(2012). Neurogenic subventricular zone stem/progenitor cells are Notch1-dependent in their active but not quiescent state J Neurosci. 32, 5654-5666
Basak, O., Giachino, C., Fiorini, E., MacDonald, H.R., and Taylor, V.
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(2013). Alpha-tanycytes of the adult hypothalamic third ventricle include distinct populations of FGF-responsive neural progenitors. Nature Communications 4, 2049
Robins. S., Stewart, I., McNay, D.E., Taylor, V., Giachino, C., Goetz, M., Ninkovic, J., Briancon, N., Maratos-Flier, E., Flier, J.S., Kokoeva, M.V., and Placzek, M.
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(2014). Molecular diversity subdivides the adult forebrain neural stem cell population. Stem Cells 32, 70-84
Giachino, C., Basak, O., Lugert, S., Knuckles, P., Obernier, K., Fiorelli, R., Frank, S., Raineteau, O., Alvarez-Buylla, A., and Taylor, V.
