Notch dimerization and gene dosage are important for normal heart development, intestinal stem cell maintenance, and splenic marginal zone B-cell homeostasis during mite infestation

Francis M. Kobia, Kristina Preusse, Quanhui Dai, Nicholas Weaver, Matthew R. Hass, Praneet Chaturvedi, Sarah J. Stein, Warren S. Pear, Zhenyu Yuan, Rhett A. Kovall, Yi Kuang, Natanel Eafergen, David Sprinzak, Brian Gebelein, Eric W. Brunskill, Raphael Kopan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Cooperative DNA binding is a key feature of transcriptional regulation. Here we examined the role of cooperativity in Notch signaling by CRISPR-mediated engineering of mice in which neither Notch1 nor Notch2 can homo- or heterodimerize, essential for cooperative binding to sequence-paired sites (SPS) located near many Notch-regulated genes. Although most known Notch-dependent phenotypes were unaffected in Notch1/2 dimer–deficient mice, a subset of tissues proved highly sensitive to loss of cooperativity. These phenotypes include heart development, compromised viability in combination with low gene dose, and the gut, developing ulcerative colitis in response to 1% dextran sulfate sodium (DSS). The most striking phenotypes—gender imbalance and splenic marginal zone B-cell lymphoma—emerged in combination with gene dose reduction or when challenged by chronic fur mite infestation. This study highlights the role of the environment in malignancy and colitis and is consistent with Notch-dependent anti-parasite immune responses being compromised in Notch dimer–deficient animals.

Original languageEnglish
Article numbere3000850
JournalPLoS Biology
Volume18
Issue number10
DOIs
StatePublished - 5 Oct 2020

Funding

FundersFunder number
CCHMC
MIHRO1 CA163353
National Science Foundation
National Institutes of HealthS10OD023410, 01DK106225
American Cancer SocietyPF-15-065-01-TBG, R01 CA215518
National Cancer InstituteT32CA009140
Bloom's Syndrome Foundation-1715822
United States-Israel Binational Science Foundation

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