Developmental Apoptosis Promotes a Disease-Related Gene Signature and Independence from CSF1R Signaling in Retinal Microglia
Developmental Apoptosis Promotes a Disease-Related Gene Signature and Independence from CSF1R Signaling in Retinal Microglia
复制标题
DOI：
10.1016/j.celrep.2019.04.062
复制
发表时间：
2019-05-14
期刊：
影响因子：
8.8
通讯作者：
Vetter, Monica L.
中科院分区：
文献类型：
--
作者：
Anderson, Sarah R.;Roberts, Jacqueline M.;Vetter, Monica L.
小胶质细胞在神经发育、衰老和疾病中具有重要的重塑功能，且有分子多样性的证据。然而，驱动小胶质细胞不同状态的信号通路和环境因素尚未完全了解。我们对中枢神经系统一个特定发育区域——小鼠视网膜的小胶质细胞进行了分析。我们发现，在整个发育过程中，视网膜小胶质细胞具有不同的转录特征，并且在出生后达到峰值密度时存在一个群体，其类似于衰老和疾病相关小胶质细胞（DAM）以及发育中白质的CD11c⁺小胶质细胞。虽然TREM2信号调节某些基因的表达，但在缺乏Bax（一种神经元死亡所需的促凋亡因子）的视网膜中，与DAM相关的特征显著减少。此外，我们发现出生后高表达CD11c的视网膜小胶质细胞对集落刺激因子1受体（CSF1R）的缺失或抑制具有抗性，而在Bax基因敲除的视网膜中，大多数小胶质细胞可以被清除。因此，发育性凋亡促进了一种与CSF1R独立性相关的小胶质细胞基因特征，该特征与发育中白质和疾病中的小胶质细胞具有共同特点。
Microglia have important remodeling functions in neurodevelopment, aging, and disease, with evidence for molecular diversity. However, the signaling pathways and environmental cues that drive diverse states of microglia are incompletely understood. We profiled microglia of a discrete developing CNS region, the murine retina. We found distinct transcriptional signatures for retinal microglia across development and peak postnatal density of a population that resembles aging and disease-associated microglia (DAM) and CD11c(+) microglia of developing white matter. While TREM2 signaling modulates the expression of select genes, the DAM-related signature is significantly reduced in retinas lacking Bax, a proapoptotic factor required for neuronal death. Furthermore, we found postnatal retinal microglia highly expressing CD11c are resistant to loss or inhibition of colony stimulating factor 1 receptor (CSF1R), while most microglia can be eliminated in Bax knockout retina. Thus, developmental apoptosis promotes a microglia gene signature linked to CSF1R independence that shares features with microglia in developing white matter and in disease.