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.
Alleles
Animals
B-Lymphocytes
/ immunology
Base Sequence
Cell Proliferation
Chromatin
/ metabolism
Dextran Sulfate
Gene Dosage
Heart
/ embryology
Heart Ventricles
/ embryology
Homeostasis
Intestines
/ pathology
Mice
Mite Infestations
/ immunology
Mites
/ physiology
Models, Biological
Protein Multimerization
Receptors, Notch
/ genetics
Spleen
/ immunology
Splenomegaly
/ immunology
Stem Cells
/ metabolism
Journal
PLoS biology
ISSN: 1545-7885
Titre abrégé: PLoS Biol
Pays: United States
ID NLM: 101183755
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
02
03
2020
accepted:
02
09
2020
revised:
15
10
2020
pubmed:
6
10
2020
medline:
15
12
2020
entrez:
5
10
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 33017398
doi: 10.1371/journal.pbio.3000850
pii: PBIOLOGY-D-20-00538
pmc: PMC7561103
doi:
Substances chimiques
Chromatin
0
Receptors, Notch
0
Dextran Sulfate
9042-14-2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
e3000850Subventions
Organisme : NCI NIH HHS
ID : R01 CA215518
Pays : United States
Organisme : NIH HHS
ID : S10 OD023410
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA009140
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA163353
Pays : United States
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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