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
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.
