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Embryonic Microglia Interact with Hypothalamic Radial Glia during Development and Upregulate the TAM Receptors MERTK
Jessica M Rosin1, Candace M Marsters2, Faizan Malik3
1Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.
Abstract:
Despite a growing appreciation for microglial influences on the developing brain, the responsiveness of microglia to insults during gestation remains less well characterized, especially in the embryo when microglia themselves are still maturing. Here, we asked if fetal microglia could coordinate an innate immune response to an exogenous insult. Using time-lapse imaging, we showed that hypothalamic microglia actively surveyed their environment by near-constant "touching" of radial glia projections. However, following an insult (i.e., IUE or AAV transduction), this seemingly passive touching became more intimate and long lasting, ultimately resulting in the retraction of radial glial projections and degeneration into small pieces. Mechanistically, the TAM receptors MERTK and AXL were upregulated in microglia following the insult, and Annexin V treatment inhibited radial glia breakage and engulfment by microglia. These data demonstrate a remarkable responsiveness of embryonic microglia to insults during gestation, a critical window for neurodevelopment.
Insights
Embryonic microglia respond to insults during gestation by interacting with radial glia. This interaction leads to glial projection retraction and degeneration, mediated by TAM receptors.
Area of Science:
- Neuroscience
- Developmental Biology
- Immunology
Background:
- Microglia are crucial for brain development.
- Microglial responses to prenatal insults are not well understood.
- Embryonic microglia are still maturing during gestation.
Purpose of the Study:
- To investigate the responsiveness of fetal microglia to exogenous insults during embryonic development.
- To determine if embryonic microglia can coordinate an innate immune response.
- To elucidate the mechanisms underlying microglial-induced changes in radial glia.
Main Methods:
- Time-lapse imaging of hypothalamic microglia in embryonic brains.
- Induction of insults using in utero electroporation (IUE) or adeno-associated virus (AAV) transduction.
- Analysis of TAM receptor (MERTK, AXL) expression.
- Inhibition studies using Annexin V treatment.
Main Results:
- Hypothalamic microglia actively survey radial glia projections via "touching."
- Insults triggered more intimate and prolonged microglial-radial glia interactions.
- Radial glial projections retracted and degenerated following insults.
- Upregulation of MERTK and AXL receptors in microglia was observed post-insult.
- Annexin V treatment prevented radial glia breakage and microglial engulfment.
Conclusions:
- Embryonic microglia exhibit significant responsiveness to insults during gestation.
- Microglial-radial glia interactions are dynamically regulated by insults.
- TAM receptors play a key role in mediating microglial responses to injury.
- These findings highlight a critical window for neurodevelopmental insults affecting microglia.
