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数量性状基因座定位为揭示小鼠组织树突状细胞数量的遗传调控提供了线索。

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

机构信息

Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.

Laboratory of Lymphocyte Dynamics, The Rockefeller University, New York, NY 10065, USA.

出版信息

Cell Rep. 2024 Jun 25;43(6):114296. doi: 10.1016/j.celrep.2024.114296. Epub 2024 May 31.

DOI:10.1016/j.celrep.2024.114296
PMID:38823019
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11726347/
Abstract

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.

摘要

为了探究遗传学对树突状细胞（DC）数量的稳态调节的影响，我们在合作分离（CC）和多样性杂交（DO）小鼠的淋巴和非淋巴组织中对 DC 及其前体细胞进行了筛选。我们报告了 30 个和 71 个具有对数优势（LOD）评分>8.18 的基因座，范围分别为 6.67 至 8.19。该分析揭示了该复杂性状的高度多基因和多效性结构，包括许多先前鉴定的 DC 发育和成熟的遗传调节因子。两个可能影响 DC 动态平衡的基因中的 SNP，一种剪接变异体 Gramd4（rs235532740）和一种错义变异体 Orai3（rs216659754），通过使用 CRISPR-Cas9 的基因编辑得到了证实。Gramd4 是 DC 动态平衡的核心调节因子，影响整个 DC 谱系，而 Orai3 调节组织中的 cDC2 数量。总体而言，这些数据揭示了大量候选基因在体内调节 DC 动态平衡。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/698b/11726347/c7454801a54a/nihms-2005231-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/698b/11726347/171ea87b2ec0/nihms-2005231-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/698b/11726347/33c5ee22d697/nihms-2005231-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/698b/11726347/1c0d40c8b28d/nihms-2005231-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/698b/11726347/6f1a3b2cea94/nihms-2005231-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/698b/11726347/5dc94661bddf/nihms-2005231-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/698b/11726347/c7454801a54a/nihms-2005231-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/698b/11726347/171ea87b2ec0/nihms-2005231-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/698b/11726347/33c5ee22d697/nihms-2005231-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/698b/11726347/1c0d40c8b28d/nihms-2005231-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/698b/11726347/6f1a3b2cea94/nihms-2005231-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/698b/11726347/5dc94661bddf/nihms-2005231-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/698b/11726347/c7454801a54a/nihms-2005231-f0006.jpg

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