Csf1r, the Colony-Stimulating Factor-1 Receptor, is a receptor tyrosine kinase. It is crucial for the differentiation and maintenance of most tissue-resident macrophages and bone-resorbing osteoclasts. Activation by endogenous cytokine ligation to its ectodomain triggers autophosphorylation of the intracellular tyrosine kinase domain, activating downstream pro-survival kinase cascades like PI3K, ERK1/2, and JNK [1].

Genetic models have provided valuable insights. For example, in Csf1rΔFIRE/ΔFIRE mice where a conserved super-enhancer (FIRE) of Csf1r is deleted, macrophage development is selectively impacted. These mice lack macrophages in the embryo, brain microglia, and resident macrophages in specific tissues such as the skin, kidney, heart, and peritoneum, while the homeostasis of other macrophage populations and monocytes remains unaffected [4]. In the context of disease, loss-of-function mutations in Csf1r are linked to neurodegeneration, like in CSF1R-related leukoencephalopathy where patients show frontotemporal dementia-like phenotypes, motor symptoms, and characteristic brain imaging features [2]. In cancer, activation of Csf1r in tumor-associate macrophages (TAMs) promotes a protumoral phenotype, and pharmacological inhibition is a promising antitumor strategy [1,3,5].

In conclusion, Csf1r is essential for the regulation of macrophage-related biological processes. Gene-knockout mouse models, such as the Csf1rΔFIRE/ΔFIRE mice, have been instrumental in understanding its tissue-specific roles. The study of Csf1r has significant implications for neurodegenerative diseases and cancer, highlighting its potential as a therapeutic target in these disease areas.

References:

1. Wen, Jiachen, Wang, Siyuan, Guo, Rongxian, Liu, Dan. 2022. CSF1R inhibitors are emerging immunotherapeutic drugs for cancer treatment. In European journal of medicinal chemistry, 245, 114884. doi:10.1016/j.ejmech.2022.114884. https://pubmed.ncbi.nlm.nih.gov/36335744/

2. Konno, Takuya, Kasanuki, Koji, Ikeuchi, Takeshi, Dickson, Dennis W, Wszolek, Zbigniew K. 2018. CSF1R-related leukoencephalopathy: A major player in primary microgliopathies. In Neurology, 91, 1092-1104. doi:10.1212/WNL.0000000000006642. https://pubmed.ncbi.nlm.nih.gov/30429277/

3. Cannarile, Michael A, Weisser, Martin, Jacob, Wolfgang, Ries, Carola H, Rüttinger, Dominik. 2017. Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy. In Journal for immunotherapy of cancer, 5, 53. doi:10.1186/s40425-017-0257-y. https://pubmed.ncbi.nlm.nih.gov/28716061/

4. Rojo, Rocío, Raper, Anna, Ozdemir, Derya D, Hume, David A, Pridans, Clare. 2019. Deletion of a Csf1r enhancer selectively impacts CSF1R expression and development of tissue macrophage populations. In Nature communications, 10, 3215. doi:10.1038/s41467-019-11053-8. https://pubmed.ncbi.nlm.nih.gov/31324781/

5. Xun, Qiuju, Wang, Zhen, Hu, Xianglong, Ding, Ke, Lu, Xiaoyun. . Small-Molecule CSF1R Inhibitors as Anticancer Agents. In Current medicinal chemistry, 27, 3944-3966. doi:10.2174/1573394715666190618121649. https://pubmed.ncbi.nlm.nih.gov/31215373/