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Mutations in the Reelin pathway are associated with abnormal expression of microglial IgG FC receptors in the cerebellar cortex

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Abstract

Microglia are the immune cells of the central nervous system involved in a variety of developmental processes, such as regulation of cell death and survival, spatial patterning, and contribute to the development of Purkinje cells (PCs) during migration. Microglia express immunoglobulin G Fc receptors (FcgRs). In this report, we describe microglial FcgR expression and its relation to abnormal PC migration in the cerebellum during development. To detect microglial FcgR, the direct anti-IgG (secondary antisera) and high concentrations of Triton X-100 were applied as a method for labeling microglial cells without the use of any specific primary antiserum. By using Acp2−/− mice, which show an excessive PC migration into the molecular layer (ml), and 3 different types of mice with a null to alter the Reelin pathway (Reeler-, Dab1 (SCM)-, and Apoer mutant mice), we studied the location of PCs and the expression of FcgRs. Wild type littermates were used as controls in all studies. We show that the expression of microglial FcgRs was absent and PCs were ectopically located in the white matter in the cerebella of all mutant mice, except for the Acp2−/− mice (PCs were located in the ml). These results suggest a role for FcgRs in the Reelin signaling pathway, not in regulating PC migration, but rather in the adaptation to an environment with a relatively large number of ectopically located PCs. However, the exact correlation between the ectopic location of PCs and lack of FcgRs in Reeler, SCM, and Apoer−/− mice and the presence of FcgRs and directed PC location in the ml in Acp2−/− mice are yet to be determined.

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Acknowledgements

The authors would like to acknowledge Science Impact (Winnipeg, Canada) for editing the manuscript.

Funding

This study was supported by grants from the Natural Sciences and Engineering Research Council (HM: NSERC Discovery Grant # RGPIN-2018-06040), Dr. Paul H.T. Thorlakson Foundation Fund (HM: Grant # 48205), and Children Hospital Research Institute of Manitoba (HM: Grant # 320035).

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Authors and Affiliations

  1. Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada

    Maryam Rahimi-Balaei, Xiaodan Jiao, Azadeh Dalvand, Shahin Shabanipour, Shayan Amiri, Jimig Kong & Hassan Marzban

  2. The Children’s Hospital Research Institute of Manitoba (CHRIM), Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada

    Maryam Rahimi-Balaei & Hassan Marzban

  3. Department of Oral Biology, University of Illinois at Chicago, Chicago, IL, USA

    Seung H. Chung

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  1. Maryam Rahimi-Balaei
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Correspondence to Hassan Marzban.

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11033_2020_5614_MOESM1_ESM.tif

Supplementary file1 (TIF 11767 kb)—Supplementary Fig. 1. Peroxidase immunostaining of cerebellar sections to show the development of FcgR+ cells. A, B, C, D. FcgR immunoperoxidase staining of a frontal section through the cerebellum at E17 showing weak immunoreactivity at the cerebellar core, as indicated by the arrowhead in a higher magnification view of the same section in “B”. FcgR immunoperoxidase reactivity is strongly outlined in microglial cell bodies at P1 (C) and P3 (D).E, F. FcgR immunoperoxidase staining of a sagittal section through the cerebellum at P10 shows strong and scattered immunoreactivity in microglia (e.g. arrow) in the white matter and cerebellar cortex, respectively. F) A higher magnification view of the same section as in “E” shows a microglial cell body (arrow) and its developing branches (arrowheads). Scale bars: 1mm (A); 250μm (B); 50μm (D applies to C); 100μm (E); 25μm (F).

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Rahimi-Balaei, M., Jiao, X., Dalvand, A. et al. Mutations in the Reelin pathway are associated with abnormal expression of microglial IgG FC receptors in the cerebellar cortex. Mol Biol Rep 47, 5323–5331 (2020). https://doi.org/10.1007/s11033-020-05614-0

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