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Cell-autonomous Jagged1 signaling as a mediator of neural stem cell differentiation

Subject Area Developmental Neurobiology
Term from 2008 to 2013
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 87528965
 
Final Report Year 2014

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.

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