Complement: The Emerging Architect of the Developing Brain

Coulthard, Liam G.; Hawksworth, Owen A.; Woodruff, Trent M.

doi:10.1016/j.tins.2018.03.009

Cited by 87 publications

(76 citation statements)

References 64 publications

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“…Here, we find that complement proteins are an important signal for RGC removal by microglia. The complement system has been implicated in development and disease with a primary focus on the ability of complement to tag synapses for pruning (Stevens et al, 2007;Schafer et al, 2012;Stephan et al, 2012;Zabel and Kirsch, 2013;Hong et al, 2016;Coulthard et al, 2018;Hawksworth et al, 2018). Complement is important for RGC-microglia interactions during postnatal periods by marking RGC synapses in the LGN for microglial engulfment (Schafer et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Complement Targets Newborn Retinal Ganglion Cells for Phagocytic Elimination by Microglia

et al. 2019

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Microglia play important roles in shaping the developing CNS, and at early stages they have been proposed to regulate progenitor proliferation, differentiation, and neuronal survival. However, these studies reveal contradictory outcomes, highlighting the complexity of these cell-cell interactions. Here, we investigate microglia function during embryonic mouse retina development, where only microglia, progenitors, and neurons are present. In both sexes, we determine that microglia primarily interact with retinal neurons and find that depletion of microglia via conditional KO of the Csf1 receptor results in increased density of retinal ganglion cells (RGCs). Pharmacological inhibition of microglia also results in an increase in RGCs, with no effect on retinal progenitor proliferation, RGC genesis, or apoptosis. We show that microglia in the embryonic retina are enriched for phagocytic markers and observe engulfment of nonapoptotic Brn3-labeled RGCs. We investigate the molecular pathways that can mediate cell engulfment by microglia and find selective downregulation of complement pathway components with microglia inhibition, and further show that C1q protein marks a subset of RGCs in the embryonic retina. KO of complement receptor 3 (CR3; Itgam), which is only expressed by microglia, results in increased RGC density, similar to what we observed after depletion or inhibition of microglia. Thus, our data suggest that microglia regulate neuron elimination in the embryonic mouse retina by complement-mediated phagocytosis of non-apoptotic newborn RGCs.

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Section: Discussionmentioning

confidence: 99%

Complement Targets Newborn Retinal Ganglion Cells for Phagocytic Elimination by Microglia

et al. 2019

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“…Alternatively, the tissue source of the other AMPs is different. Based on the observation that in other species immune genes can be expressed in the neurons [18,19], we used a pan-neuronal-GAL4 line, to express RNAi against the AMPs in the nervous system and measured long-term courtship suppression memory (Fig 4A). As indicated before the expression of DptB RNAi in neurons had no effect, however, surprisingly, the expression of GNBP-like3 RNAi in neurons significantly (p<0.001) impaired long-term courtship suppression memory (Fig 4A).…”

Section: Gnbp-like 3 Is Required In Neurons For Long-term Memorymentioning

confidence: 99%

Antimicrobial peptides modulate long-term memory

Azpeleta

Weng

et al. 2018

Preprint

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Antimicrobial peptides act as a host defense mechanism and regulate the commensal microbiome.To obtain a comprehensive view of genes contributing to long-term memory we performed mRNA sequencing from single Drosophila heads following behavioral training that produces long-lasting memory. Surprisingly, we find that two immune peptides with antimicrobial activity, Diptericin B and Gram-Negative Bacteria Binding Protein like 3, regulate long-term but not short-term memory or instinctive behavior in Drosophila. The cellular requirement of these two peptides is distinct: head fat body for DptB, and neurons for GNBP-like3. That antimicrobial peptides influence memory provides a novel example of the emerging link between the immune and nervous systems and reveals that some immune peptides may have been repurposed in the nervous system. Author summaryIt is becoming evident that the nervous system and immune system share not only some of the same molecular logic but also the same components. Here, we report a novel and unanticipated example of how immune genes influence nervous system function. During exploring how Drosophila form longlasting memories of certain experiences, we have found that antimicrobial peptides that fight bacteria in the body, are expressed in the head, and control whether an animal would form long-term memory of a food source or a mating partner. Antimicrobial peptides are detected in the brain of many species and has often been associated with dysfunction of the nervous system. This and other recent works, provide an explanation to why antimicrobial peptides may be expressed in the brain: they regulate normal functions of the brain. Both eating, and mating engage the immune system in preparation of exposure to external agents including bacteria. We speculate antimicrobial peptides were upregulated in the body to deal with immune challenges and over evolutionary time some of them are co-adopted to convey specific information about food or mating to the brain.

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“…However, apart from C4A , surprisingly little is known about the extent to which the complement system is dysregulated and implicated in SCZ-whether it represents a key disease-relevant pathway and whether it interacts with other established genetic risk factors. Furthermore, while overactivation of C4A and the complement system is hypothesized to lead to excessive synaptic pruning [9][10][11][12][13] , it is unclear as of yet whether complement-mediated pruning in higher association areas like frontal cortex is indeed the biological mechanism through which C4A imparts risk for SCZ. Complicating matters, the lack of evolutionary conservation has hindered direct investigation in animal models like mice, which possess only one functional copy of C4 that is a combination of C4A and C4B isotypes.…”

Section: Introductionmentioning

confidence: 99%

Brain gene co-expression networks link complement signaling with convergent synaptic pathology in schizophrenia

Kim

Haney

Zhang

et al. 2020

Preprint

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Genome-wide association studies have successfully identified hundreds of genomic regions associated with schizophrenia (SCZ). Subsequent fine-mapping of the strongest association signal, which lies in the major histocompatibility complex (MHC) locus, found that risk for SCZ is partially mediated by complex structural variation of the complement component 4 ( C4 ) genes and resulting increased expression of C4A . Although C4A is believed to partake in synaptic pruning, its precise function in the human brain-and its relation to other SCZ risk factors-remains difficult to examine, due to lack of an appropriate experimental system and lack of evolutionary conservation in model organisms. Here we perform a large-scale functional genomic investigation of the human frontal cortex to characterize the systems-level architecture of C4A co-expression and how this network is remodeled with increased C4A copy number. We identify a putative transcriptomic signature of synaptic pruning as well as spatiotemporal and sex differences in C4A co-expression with largest effects observed in frontal cortical brain regions of middle-aged males. We also find that negative, but not positive, co-expression partners of C4A exhibit substantial enrichment for SNP-heritability in SCZ. In line with this finding, there is limited evidence that the complement system is a core SCZ-relevant pathway in comparison to synaptic components. Overall, our results highlight human brain-specific function of C4A and strong and specific convergence of polygenic effects in SCZ pathophysiology.

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Complement: The Emerging Architect of the Developing Brain

Cited by 87 publications

References 64 publications

Complement Targets Newborn Retinal Ganglion Cells for Phagocytic Elimination by Microglia

Complement Targets Newborn Retinal Ganglion Cells for Phagocytic Elimination by Microglia

Antimicrobial peptides modulate long-term memory

Brain gene co-expression networks link complement signaling with convergent synaptic pathology in schizophrenia

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