Hoover Camden A, Dennen John, Gan Dailin, Li Jun, Smith Cody J
bioRxiv. 2025 Jul 31:2025.07.30.667678. doi: 10.1101/2025.07.30.667678.
Embryonic development is precisely shaped by maternal and zygotic factors. These maternal factors exert their influence through maternal effects, a phenomenon where an offspring's phenotype is determined, at least in part, by the mother's environment and genotype. While environmental maternal effects can cause phenotypes that present both early and later in life, genetic maternal effects generally induce phenotypes in the earliest embryonic stages. Here, we reveal a genetic maternal effect that influences the development of cells that arise after early embryogenesis, highlighting that specific cell types can be susceptible to late-onset genetic maternal effects. Using zebrafish to study microglia, the resident immune cells of the brain, we identified a mutation in that exhibits a maternal effect phenotype that presents as a reduction of microglia in the brain and precursors in the yolk sac. We demonstrate that is expressed in microglia and their yolk sac precursors and is maternally-loaded. We show that restoration via embryonic injection reverses the maternal effect on microglia and yolk sac cells in mutants. To identify additional genes interacting with , we nominated genes from scRNA sequencing analysis of mouse embryonic microglia to perform a genetic screen using CRISPR mutagenesis and a custom-built robot that captures confocal images of the zebrafish brain in high-throughput. This screen identified and as modifiers of microglia abundance in the embryonic brain, which we demonstrated are also expressed in zebrafish microglia. Transcriptional and mutant analyses with these new modifiers suggest that positively regulates transcription. These results demonstrate that microglia are susceptible to genetic maternal effects, in addition to their known sensitivity to environmental maternal effects. Our findings reveal a late-onset phenotype associated with the maternal genotype, expanding the recognized impact of genetic maternal effects beyond initial embryo viability and into long-term vigor.
胚胎发育由母体和合子因素精确塑造。这些母体因素通过母体效应发挥作用，母体效应是指后代的表型至少部分由母亲的环境和基因型决定的现象。虽然环境母体效应可导致在生命早期和后期出现的表型，但遗传母体效应通常在胚胎发育的最早阶段诱导表型。在这里，我们揭示了一种遗传母体效应，它影响早期胚胎发生后出现的细胞的发育，突出表明特定细胞类型可能易受迟发性遗传母体效应的影响。利用斑马鱼研究大脑中的常驻免疫细胞小胶质细胞，我们在[基因名称]中鉴定出一个突变，该突变表现出母体效应表型，表现为大脑中小胶质细胞和卵黄囊中前体细胞减少。我们证明[基因名称]在小胶质细胞及其卵黄囊前体细胞中表达，并且是母体加载的。我们表明，通过胚胎注射恢复[基因名称]可逆转[突变体名称]突变体中母体对小胶质细胞和卵黄囊细胞的效应。为了鉴定与[基因名称]相互作用的其他基因，我们从小鼠胚胎小胶质细胞的单细胞RNA测序分析中提名基因，使用CRISPR诱变和一个定制的机器人进行遗传筛选，该机器人可高通量捕获斑马鱼大脑的共聚焦图像。该筛选鉴定出[基因名称1]和[基因名称2]作为胚胎大脑中小胶质细胞丰度的调节因子，我们证明它们也在斑马鱼小胶质细胞中表达。对这些新调节因子的转录和突变分析表明，[基因名称1]正向调节[基因名称2]的转录。这些结果表明，小胶质细胞除了对环境母体效应已知的敏感性外，还易受遗传母体效应的影响。我们的发现揭示了一种与母体基因型相关的迟发表型，将遗传母体效应的公认影响从最初的胚胎活力扩展到长期活力。
