Quantitative trait loci mapping provides insights into the genetic regulation of dendritic cell numbers in mouse tissues

Thiago Y. Oliveira; Julia Merkenschlager; Thomas Eisenreich; Juliana Bortolatto; Kai-Hui Yao; Daniel M. Gatti; Gary A. Churchill; Michel C. Nussenzweig; Gaëlle Breton

Cell Reports (Jun 2024)

Quantitative trait loci mapping provides insights into the genetic regulation of dendritic cell numbers in mouse tissues

Thiago Y. Oliveira,
Julia Merkenschlager,
Thomas Eisenreich,
Juliana Bortolatto,
Kai-Hui Yao,
Daniel M. Gatti,
Gary A. Churchill,
Michel C. Nussenzweig,
Gaëlle Breton

Affiliations

Thiago Y. Oliveira: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA
Julia Merkenschlager: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA
Thomas Eisenreich: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA
Juliana Bortolatto: Laboratory of Lymphocyte Dynamics, The Rockefeller University, New York, NY 10065, USA
Kai-Hui Yao: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA
Daniel M. Gatti: The Jackson Laboratory, Bar Harbor, ME 04609, USA
Gary A. Churchill: The Jackson Laboratory, Bar Harbor, ME 04609, USA
Michel C. Nussenzweig: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA; Howard Hughes Medical Institute (HHMI), The Rockefeller University, New York, NY 10065, USA; Corresponding author
Gaëlle Breton: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA; Corresponding author

Journal volume & issue: Vol. 43, no. 6
p. 114296

Abstract

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Summary: To explore the influence of genetics on homeostatic regulation of dendritic cell (DC) numbers, we present a screen of DCs and their progenitors in lymphoid and non-lymphoid tissues in Collaborative Cross (CC) and Diversity Outbred (DO) mice. We report 30 and 71 loci with logarithm of the odds (LOD) scores >8.18 and ranging from 6.67 to 8.19, respectively. The analysis reveals the highly polygenic and pleiotropic architecture of this complex trait, including many of the previously identified genetic regulators of DC development and maturation. Two SNPs in genes potentially underlying variation in DC homeostasis, a splice variant in Gramd4 (rs235532740) and a missense variant in Orai3 (rs216659754), are confirmed by gene editing using CRISPR-Cas9. Gramd4 is a central regulator of DC homeostasis that impacts the entire DC lineage, and Orai3 regulates cDC2 numbers in tissues. Overall, the data reveal a large number of candidate genes regulating DC homeostasis in vivo.

CP: Immunology

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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Abstract

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