The surveillance role of embryonic microglia during neurogenesis
The work by Rosin et al has advanced our understanding of how radial glial cells (RGC) during embryonic development are constantly under the surveillance of embryonic microglia in hypothalamus and its major role in removing the RGC during insults to maintain a healthy population of RGC. RGC produces most of the neurons and glial cells in the brain. Emerging evidence suggests that microglia plays a major role postnatally in removing supernumerary neurons and also involved in sculpting of neuronal synapses. Microglia recognises receptors or ligands expressed by the neurons to mediate its response. For instance, it has been shown that recently that c1q complementary pathway is involved in synapse pruning and in the pathogenesis of Alzheimer’s diseases whilst the CD47-SIRP pathway protects the synapses from excessive microglia pruning. The work of Rosin et al has shown the surveillance role of microglia in normal embryonic development whereby microglia constantly wrap their processes around the projections of RGCs with time durations for less than 15 minutes. In contrast, when an exogenous insult was introduced either by electroporation or by virus injections, the interaction between microglia and RGCs lasted for hours culminating in the phagocytosis of RGCs. The authors found that RGCs express phosphatidylserine on the outer leaflet of the membrane, which acts as a “eat me” signal to recruit microglia that specifically upregulate the expression of TAM family of receptors, MERTK and AXL to mediate the phagocytosis. The authors speculate that this checkpoint mechanism by embryonic microglia may help in keeping healthy RGCs that produce multiple cell types in the hypothalamus. The authors did not address some of the key issues that are described below.
All the cells that express PS outside on the membrane need not necessarily have to undergo phagocytosis, as some of them may be viable which is dependent on the kinetics of the intracellular calcium. Viable cells show rapid kinetics in minutes whilst the dying cells exhibit slow kinetics. Besides that, the spatial distribution and density of PS dictates whether the cells undergo phagocytosis or not. Moreover, PS binds to different families of receptors and adaptor proteins such as GAS6 indirectly mediating some interactions. Interestingly, the wild type E15.5 embryonic microglia expresses a comparatively similar level of MERTK as that of insulted one (3 hours post). Given the insult is local, the author did not show the numbers of activated microglia as a function of distance from the infection site. Moreover, the authors also did not measure the number of RGCs phagocytosed or the phagosomes per unit area and hence it is difficult to compare between two different treatments and partial rescue experiments with annexin. In the case of partial rescue, it is surprising why the authors did not attempt to target PS with monoclonal antibodies. It would have been more comprehensive had the authors tried to see whether these differential changes hold true in other regions of the brain by insulting the lateral ventricle that lines the cortex. Future studies will shed light on whether the same mechanism of microglial activation happens in other regions of the brain or would they differ.
Original article: “Embryonic Microglia Interact with Hypothalamic Radial Glia during Development and Upregulate the TAM Receptors MERTK and AXL following an Insult” — Cell reports, 2021 (PMID no: 33406432)
