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.

Autor: 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
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Zdroj: PLoS Biology, Vol 18, Iss 10, p e3000850 (2020)
Druh dokumentu: article
ISSN: 1544-9173
1545-7885
DOI: 10.1371/journal.pbio.3000850
Popis: 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.
Databáze: Directory of Open Access Journals
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