In mammals, microglial cells of the central nervous system are responsible for the normal clearance of dead brain cells. TAM-receptor proteins have now been found to mediate this function. See Letter p.240
Cell-surface receptors are specialized molecules that respond to precise signals, so that environmental input elicits commensurate responses. On page 240 of this issue, Fourgeaud et al.1 describe how they manipulated the mouse genome to delete receptor proteins of the TAM family from microglia — a type of brain cell distantly related to the resident inflammatory cells found in tissues such as the skin, spleen and liver. The results provide startling insight into the process by which the adult brain generates new neurons, and open up avenues for studying microglia.
TAM receptors (named from the first letters of the member proteins Tyro3, Axl and Mer) are evolutionarily recent, appearing first in the invertebrate sea squirts. Newly emerged gene families often have highly refined roles, and their function is commonly dispensable for embryonic development. People (or genetically engineered mice) with defective TAM genes develop normally but show varied effects later in life2. For example, humans or rodents deficient in the Mer gene develop a form of retinitis pigmentosa. This degenerative eye disease occurs because rod photoreceptor cells (RPCs) accumulate toxic by-products of chemical reactions through which light is converted to nerve impulses. This waste material is removed through engulfment of the RPCs' outer segment by retinal pigment epithelial cells; without Mer, this process fails and RPCs die.
Another example is that mice lacking all three TAM receptors show male infertility, because vast numbers of superfluous germ cells die and accumulate in the testes, leading to degeneration of the remaining, otherwise-viable germ cells. Mice that lack individual receptors or ligands of the TAM system also show blood-clotting defects, and those deficient in all three receptors develop widespread autoimmune responses that are reminiscent of the human disease systemic lupus erythematosus3. Thus, TAM-receptor signalling is used in a wide variety of disparate functions primarily associated with the removal of dying cells and waste material.
Mice that lack all three TAM receptors are normal at birth, indicating that these proteins are not required to eliminate dead cells during embryonic development2. But the TAM receptors are involved in a variant form of this elimination mechanism to achieve dynamic tissue remodelling throughout life2. This cell-corpse removal, as well as that occurring in the wake of an infection, is carried out in vertebrates by phagocytes ('cells that eat'), and particularly by white blood cells termed macrophages ('big eaters'). Cells that are undergoing apoptotic cell death expose surface markers ('eat me' signals) that alert nearby phagocytes to engulf and dispose of the cell corpse. But, in contrast to receptors that directly bind cells displaying these markers, TAM receptors use adaptor proteins, or ligands, that bind both the marker on the cell to be removed and the TAM receptor on the phagocyte. These adaptors are called growth-arrest-specific protein 6 (Gas6) and protein S.
Fourgeaud et al. examined the function of TAM receptors in brain microglia — cells whose origin and competencies are only now becoming clear. Microglia are derived from primitive macrophages that enter the embryo from the yolk sac early in development, become distributed throughout the embryo as resident macrophages, and guide organ development. In the embryonic brain, which is populated by microglia from day 10 of gestation in mice and from gestational week 4.5 in humans4, exuberant production of redundant cells keeps microglia busy clearing corpses5. The brain forms normally without TAM receptors, and Fourgeaud and colleagues wondered what the molecules' roles might be in adult life.
The study initially focused on two brain regions in which neurons are continuously being born and that are therefore designated neurogenic niches6. One of these niches produces neurons to replenish olfactory neurons, which support the sense of smell. Neurons from the second niche become integrated into regions associated with memory and learning. As with many generative tissues, the neurogenic niches produce an excess of progenitor cells (which have the potential to develop into neurons), most of which die. Speculation held that microglia cleared these cell corpses, and it seemed plausible that neurogenesis would fail if corpse removal was impaired7. Previous research8 using mice that lacked all three TAM receptors in all tissues suggested an alternative idea: that neurogenesis is suppressed as a result of excessive inflammatory reactions by microglia with deficient TAM signalling. However, the state of the neurogenic niches without microglial TAM receptors remained unresolved.
Fourgeaud and colleagues' investigation of mice that lacked both Mer and Axl initially confirmed the predicted phagocytic defect: neuron progenitors showing markers of apoptotic death accumulated to a striking degree, whereas these dying cells were not seen in wild-type mice, nor were they seen in regions other than the niches. But the authors' analysis of neurogenesis yielded a shock: new neurons in the olfactory region increased by 70% in the mice lacking Mer and Axl.
An explanation for this result came from another study9, which showed that microglia in regions of the mouse brain damaged by stroke engulfed viable neurons that displayed 'eat me' signals because of stress, not cell death. This study also found that if the uptake of these neurons by phagocytes was blocked, and thus their death by 'phagoptosis' prevented, the severity of stroke was reduced. Fourgeaud and colleagues' interpretation of these combined data is that phagoptosis can be observed in the healthy brain during neurogenesis (Fig. 1). Future work to determine the effects of augmented neurogenesis will be informative.
The Mer- and Axl-deficient microglia showed other changes as well. Microglia are noted for their delicate, branched processes, which are continually in motion, monitoring synapses (connections between nerve cells)10. Fourgeaud et al. show that TAM receptors are essential for the processes to be fully motile. Would lack of one or more of these receptors change microglial cells' ability to carry out their manifold tasks in aid of synaptic networks? Further revelations are likely as the TAM-receptor story unfolds and is integrated with findings from other microglial signalling systems.Footnote 1
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Gomez Perdiguero, E., Schulz, C. & Geissmann, F. Glia 61, 112–120 (2013).
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Sierra, A., Tremblay, M.-E. & Wake, H. Front. Cell. Neurosci. 8, 240 (2014).
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