Genome-Wide Analysis of N1ICD/RBPJ Targets In Vivo Reveals Direct Transcriptional Regulation of Wnt, SHH, and Hippo Pathway Effectors by Notch1 (original) (raw)

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,

These authors contributed equally to this work

The Jackson Laboratory

, Bar Harbor, Maine,

USA

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,

These authors contributed equally to this work

The Jackson Laboratory

, Bar Harbor, Maine,

USA

Search for other works by this author on:

,

These authors contributed equally to this work

The Jackson Laboratory

, Bar Harbor, Maine,

USA

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,

Natalia Aliakseeuna Shylo

The Jackson Laboratory

, Bar Harbor, Maine,

USA

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The Jackson Laboratory

, Bar Harbor, Maine,

USA

Correspondence: Kyuson Yun, Ph.D., The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609, USA. Telephone: 207-288-6825; Fax: (207) 288-6078; e-mail: Kyuson.yun@jax.org

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Received:

17 October 2011

Accepted:

20 December 2011

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Yaochen Li, Matthew Aaron Hibbs, Ashley Lauren Gard, Natalia Aliakseeuna Shylo, Kyuson Yun, Genome-Wide Analysis of N1ICD/RBPJ Targets In Vivo Reveals Direct Transcriptional Regulation of Wnt, SHH, and Hippo Pathway Effectors by Notch1, Stem Cells, Volume 30, Issue 4, April 2012, Pages 741–752, https://doi.org/10.1002/stem.1030
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Abstract

The Notch pathway plays a pivotal role in regulating cell fate decisions in many stem cell systems. However, the full repertoire of Notch target genes in vivo and the mechanisms through which this pathway activity is integrated with other signaling pathways are largely unknown. Here, we report a transgenic mouse in which the activation of the Notch pathway massively expands the neural stem cell (NSC) pool in a cell context-dependent manner. Using this in vivo system, we identify direct targets of RBPJ/N1ICD in cortical NSCs at a genome-wide level through combined ChIP-Seq and transcriptome analyses. Through a highly conservative analysis of these datasets, we identified 98 genes that are directly regulated by N1ICD/RPBJ in vivo. These include many transcription factors that are known to be critical for NSC self-renewal (Sox2, Pax6, Tlx, and Id4) and the transcriptional effectors of the Wnt, SHH, and Hippo pathways, TCF4, Gli2, Gli3, Yap1, and Tead2. Since little is known about the function of the Hippo-Yap pathway in NSCs, we analyzed Yap1 expression and function in NSCs. We show that Yap1 expression is restricted to the stem cell compartment in the developing forebrain and that its expression is sufficient to rescue Notch pathway inhibition in NSC self-renewal assays. Together, results of this study reveal a previously underappreciated complexity and breadth of Notch1 targets in vivo and show direct interaction between Notch and Hippo-Yap pathways in NSCs.

Disclosure of potential conflicts of interest is found at the end of this article.

Copyright © 2012 AlphaMed Press

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open\_access/funder\_policies/chorus/standard\_publication\_model)

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