Integrative genomics of microglia implicates DLG4 (PSD95) in the white matter development of preterm infants (original) (raw)
Related papers
Preterm birth places newborn infants in an adverse environment that leads to brain injury linked to neuroinflammation. To characterise this pathology, we present a translational bioinformatics investigation, with integration of human and mouse molecular and neuroimaging datasets to provide a deeper understanding of the role of microglia in preterm white matter damage. We examined preterm neuroinflammation in a mouse model of encephalopathy of prematurity induced by IL1B exposure, carrying out a gene network analysis of the cell-specific transcriptomic response to injury, which we extended to analysis of protein-protein interactions, transcription factors, and human brain gene expression, including translation to preterm infants by means of imaging-genetics approaches in the brain. We identified the endogenous synthesis of DLG4 (PSD95) protein by microglia in mouse and human, modulated by inflammation and development. Systemic genetic variation in DLG4 was associated with structural ...
Gene regulatory networks underlying human microglia maturation
bioRxiv, 2021
The fetal period is a critical time for brain development, characterized by neurogenesis, neural migration, and synaptogenesis1-3. Microglia, the tissue resident macrophages of the brain, are observed as early as the fourth week of gestation4 and are thought to engage in a variety of processes essential for brain development and homeostasis5-11. Conversely, microglia phenotypes are highly regulated by the brain environment12-14. Mechanisms by which human brain development influences the maturation of microglia and microglia potential contribution to neurodevelopmental disorders remain poorly understood. Here, we performed transcriptomic analysis of human fetal and postnatal microglia and corresponding cortical tissue to define age-specific brain environmental factors that may drive microglia phenotypes. Comparative analysis of open chromatin profiles using bulk and single-cell methods in conjunction with a new computational approach that integrates epigenomic and single-cell RNA-seq...
Premature birth is the commonest cause of death and disability in young children. Diffuse white matter injury (DWMI), provoked by inflammatory insults accompanying prematurity, is associated with increased risk of neurodevelopmental disorders - such as autism spectrum disorders - and is due to maturation arrest in oligodendrocyte precursors (OPCs). The lack of therapeutic solutions is a strong impetus to unveil the molecular mechanisms underlying neuroinflammation impact on OPC cell fate. We used a validated mouse model of DWMI, induced by systemic- and neuro-inflammation - as observed in preterm infants - and based on interleukin-1B administration from postnatal day P1 to P5. Using integrated genome-wide approaches we showed that neuroinflammation induced limited epigenomic disturbances in OPCs, but marked transcriptomic alterations of genes of the immune/inflammatory pathways. We found that these genes were expressed in control OPCs and physiologically downregulated between P3-P10...
Microglia toxicity in preterm brain injury
Reproductive Toxicology, 2014
Microglia are the resident phagocytic cells of the central nervous system. During brain development they are also imperative for apoptosis of excessive neurons, synaptic pruning, phagocytosis of debris and maintaining brain homeostasis. Brain damage results in a fast and dynamic microglia reaction, which can influence the extent and distribution of subsequent neuronal dysfunction. As a consequence, microglia responses can promote tissue protection and repair following brain injury, or become detrimental for the tissue integrity and functionality. In this review, we will describe microglia responses in the human developing brain in association with injury, with particular focus on the preterm infant. We also explore microglia responses and mechanisms of microglia toxicity in animal models of preterm white matter injury and in vitro primary microglia cell culture experiments.
Neurobiology of disease, 2017
Maternal inflammation during pregnancy can have detrimental effects on embryonic development that persist during adulthood. However, the underlying mechanisms and insights in the responsible cell types are still largely unknown. Here we report the effect of maternal inflammation on fetal microglia, the innate immune cells of the central nervous system (CNS). In mice, a challenge with LPS during late gestation stages (days 15-16-17) induced a pro-inflammatory response in fetal microglia. Adult whole brain microglia of mice that were exposed to LPS during embryonic development displayed a persistent reduction in pro-inflammatory activation in response to a re-challenge with LPS. In contrast, hippocampal microglia of these mice displayed an increased inflammatory response to an LPS re-challenge. In addition, a reduced expression of brain-derived neurotrophic factor (BDNF) was observed in hippocampal microglia of LPS-offspring. Microglia-derived BDNF has been shown to be important for l...
Frontiers in neurology, 2018
Microglial cells form a context-dependent network of brain immunoeffector cells. Despite their indispensable roles, unresolved questions exist around biomarker discovery relevant to their cellular localization, self-renewing potential, and brain developmental dynamics. To resolve the existent gap in the annotation of candidate biomarkers, we conducted a meta-analysis of brain cells using available high-throughput data sets for deciphering microglia-specific expression profiles. We have identified 3,290 significant genes specific to microglia and further selected the top 20 dysregulated genes on the basis of -value and logFC. To this list, we added 7 known microglia-specific markers making the candidate list comprising 27 genes for further downstream analyses. Next, we established a connectome of these potential markers with their putative protein partners, which demonstrated strong associations of upregulated genes like Dedicator of cytokinesis 2 () with early/mature microglial mark...
Microglial contribution to the pathology of neurodevelopmental disorders in humans
Acta Neuropathologica, 2023
Microglia are the brain's resident macrophages, which guide various developmental processes crucial for brain maturation, activity, and plasticity. Microglial progenitors enter the telencephalic wall by the 4th postconceptional week and colonise the fetal brain in a manner that spatiotemporally tracks key neurodevelopmental processes in humans. However, much of what we know about how microglia shape neurodevelopment comes from rodent studies. Multiple differences exist between human and rodent microglia warranting further focus on the human condition, particularly as microglia are emerging as critically involved in the pathological signature of various cognitive and neurodevelopmental disorders. In this article, we review the evidence supporting microglial involvement in basic neurodevelopmental processes by focusing on the human species. We next concur on the neuropathological evidence demonstrating whether and how microglia contribute to the aetiology of two neurodevelopmental disorders: autism spectrum conditions and schizophrenia. Next, we highlight how recent technologies have revolutionised our understanding of microglial biology with a focus on how these tools can help us elucidate at unprecedented resolution the links between microglia and neurodevelopmental disorders. We conclude by reviewing which current treatment approaches have shown most promise towards targeting microglia in neurodevelopmental disorders and suggest novel avenues for future consideration.
Microglia-Mediated Neurodegeneration in Perinatal Brain Injuries
Biomolecules, 2021
Perinatal brain injuries, including encephalopathy related to fetal growth restriction, encephalopathy of prematurity, neonatal encephalopathy of the term neonate, and neonatal stroke, are a major cause of neurodevelopmental disorders. They trigger cellular and molecular cascades that lead in many cases to permanent motor, cognitive, and/or behavioral deficits. Damage includes neuronal degeneration, selective loss of subclasses of interneurons, blocked maturation of oligodendrocyte progenitor cells leading to dysmyelination, axonopathy and very likely synaptopathy, leading to impaired connectivity. The nature and severity of changes vary according to the type and severity of insult and maturation stage of the brain. Microglial activation has been demonstrated almost ubiquitously in perinatal brain injuries and these responses are key cell orchestrators of brain pathology but also attempts at repair. These divergent roles are facilitated by a diverse suite of transcriptional profiles...
Microglia shape corpus callosum axon tract fasciculation: functional impact of prenatal inflammation
European Journal of Neuroscience, 2014
Microglia colonise the brain parenchyma at early stages of development and accumulate in specific regions where they participate in cell death, angiogenesis, neurogenesis and synapse elimination. A recurring feature of embryonic microglial is their association with developing axon tracts, which, together with in vitro data, supports the idea of a physiological role for microglia in neurite development. Yet the demonstration of this role of microglia is lacking. Here, we have studied the consequences of microglial dysfunction on the formation of the corpus callosum, the largest commissure of the mammalian brain, which shows consistent microglial accumulation during development. We studied two models of microglial dysfunction: the loss-of-function of DAP12, a key microglial-specific signalling molecule, and a model of maternal inflammation by peritoneal injection of lipopolysaccharide at embryonic day (E) 15.5. We also took advantage of the Pu.1 À/À mouse line, which is devoid of microglia. We performed transcriptional profiling of maternally inflamed and Dap12-mutant microglia at E17.5. The two treatments principally down-regulated genes involved in nervous system development and function, particularly in neurite formation. We then analysed the developmental consequences of these microglial dysfunctions on the formation of the corpus callosum. We show that all three models of altered microglial activity resulted in the defasciculation of dorsal callosal axons. Our study demonstrates that microglia display a neurite-development-promoting function and are genuine actors of corpus callosum development. It further shows that microglial activation impinges on this function, thereby revealing that prenatal inflammation impairs neuronal development through a loss of trophic support.