Mater Research Institute, University of Queensland, Woolloongabba, Queensland, Australia.
Centre for Inflammation Research, The University of Edinburgh, Edinburgh, United Kingdom.
J Leukoc Biol. 2020 Feb;107(2):205-219. doi: 10.1002/JLB.MR0519-143R. Epub 2019 Jul 22.
Mϕ proliferation, differentiation, and survival are controlled by signals from the Mϕ CSF receptor (CSF1R). Mono-allelic gain-of-function mutations in CSF1R in humans are associated with an autosomal-dominant leukodystrophy and bi-allelic loss-of-function mutations with recessive skeletal dysplasia, brain disorders, and developmental anomalies. Most of the phenotypes observed in these human disease states are also observed in mice and rats with loss-of-function mutations in Csf1r or in Csf1 encoding one of its two ligands. Studies in rodent models also highlight the importance of genetic background and likely epistatic interactions between Csf1r and other loci. The impacts of Csf1r mutations on the brain are usually attributed solely to direct impacts on microglial number and function. However, analysis of hypomorphic Csf1r mutants in mice and several other lines of evidence suggest that primary hydrocephalus and loss of the physiological functions of Mϕs in the periphery contribute to the development of brain pathology. In this review, we outline the evidence that CSF1R is expressed exclusively in mononuclear phagocytes and explore the mechanisms linking CSF1R mutations to pleiotropic impacts on postnatal growth and development.
Mϕ 增殖、分化和存活受 Mϕ CSF 受体（CSF1R）的信号控制。人类 CSF1R 的单等位基因突变与常染色体显性白质营养不良有关，双等位基因突变与隐性骨骼发育不良、脑部疾病和发育异常有关。在这些人类疾病状态中观察到的大多数表型也在 Csf1r 缺失功能突变或其两种配体之一的 Csf1 编码的小鼠和大鼠中观察到。啮齿动物模型的研究还强调了遗传背景的重要性，以及 Csf1r 和其他基因座之间可能存在上位性相互作用。Csf1r 突变对大脑的影响通常仅归因于对小胶质细胞数量和功能的直接影响。然而，对小鼠的低功能 Csf1r 突变体的分析和其他一些证据表明，原发性脑积水和外周 Mϕ 生理功能的丧失导致了脑病理学的发展。在这篇综述中，我们概述了 CSF1R 仅在单核吞噬细胞中表达的证据，并探讨了将 CSF1R 突变与对出生后生长和发育的多效性影响联系起来的机制。
