23 research outputs found
GPR56 Functions Together with α3β1 Integrin in Regulating Cerebral Cortical Development
Loss of function mutations in GPR56, which encodes a G protein-coupled receptor, cause a specific human brain malformation called bilateral frontoparietal polymicrogyria (BFPP). Studies from BFPP postmortem brain tissue and Gpr56 knockout mice have previously showed that GPR56 deletion leads to breaches in the pial basement membrane (BM) and neuronal ectopias during cerebral cortical development. Since α3β1 integrin also plays a role in pial BM assembly and maintenance, we evaluated whether it functions together with GPR56 in regulating the same developmental process. We reveal that loss of α3 integrin enhances the cortical phenotype associated with Gpr56 deletion, and that neuronal overmigration through a breached pial BM occurs earlier in double knockout than in Gpr56 single knockout mice. These observations provide compelling evidence of the synergism of GPR56 and α3β1 integrin in regulating the development of cerebral cortex
Recommended from our members
Single-Cell RNA Sequencing of Microglia throughout the Mouse Lifespan and in the Injured Brain Reveals Complex Cell-State Changes.
Microglia, the resident immune cells of the brain, rapidly change states in response to their environment, but we lack molecular and functional signatures of different microglial populations. Here, we analyzed the RNA expression patterns of more than 76,000 individual microglia in mice during development, in old age, and after brain injury. Our analysis uncovered at least nine transcriptionally distinct microglial states, which expressed unique sets of genes and were localized in the brain using specific markers. The greatest microglial heterogeneity was found at young ages; however, several states-including chemokine-enriched inflammatory microglia-persisted throughout the lifespan or increased in the aged brain. Multiple reactive microglial subtypes were also found following demyelinating injury in mice, at least one of which was also found in human multiple sclerosis lesions. These distinct microglia signatures can be used to better understand microglia function and to identify and manipulate specific subpopulations in health and disease
Recommended from our members
Individual polychlorinated biphenyl (PCB) congeners interact to disrupt thyroid hormone action during development
Nearly 20% of U.S. children are reported to have neurobehavioral deficits in part linked to environmental exposure to industrial chemicals like polychlorinated biphenyls (PCBs). PCB exposure is associated with neurotoxicity including both reduced IQ and response inhibition. PCBs may affect normal brain development by acting on the thyroid hormone (TH) system, either by reducing serum TH levels and/or by interfering with TH receptors (TRs). A critical endpoint, dependent upon sufficient TH, is maturation of oligodendrocytes during development and therefore subject to disruption by PCBs. Due to the complexity of the brain we used both in vitro and in vivo approaches to understand the mechanism of PCBs interfering with TH action. Previous work in our lab has demonstrated that metabolism of PCB congeners is necessary for them to act on the TR in vitro. In neonatal rat livers, we evaluated the TR-agonistic properties of PCBs on TR-dependent gene expression in the presence and absence of metabolism. We found that expression of TH target genes in PCB-exposed livers varied between different congener combinations and was independent of the PCB-induced reduction in circulating T4 levels. Further evaluation of global changes in gene expression between a commercial PCB mixture A1254 and hypothyroidism revealed that only 25% of TH-responsive genes also respond to PCB exposure. Individual congeners accounted for only half of the A1254 effects on TH-regulated genes, suggesting that unidentified congeners or metabolites are affecting TH action. In the neonatal brain, we evaluated the congener-specific effects on a TH- sensitive endpoint during development, the white matter cell numbers in the corpus callosum (CC). In the CC, hypothyroidism decreased oligodendrocytes by about 80%. A1254 achieved a 35% reduction in oligodendrocytes; an effect mediated by a mixture of individual congeners. Hypothyroidism and A1254 exposure increased astrocyte numbers by 30%, but the effect of A1254 seems to be mediated by yet another subset of PCB congeners independent of the TH serum levels. PCB exposure has a differential effect on glial cell differentiation in the CC compared to hypothyroidism that is congener-specific as well as region-specific. Both changes in glia cells during development are not observed in adulthood. The disruption of glia cell ratio in the CC by PCBs could lead to diminished CNS functionality during a critical window of neonatal development
Recommended from our members
Adhesion G Protein-Coupled Receptors as Drug Targets for Neurological Diseases
The family of adhesion G protein-coupled receptors (aGPCRs) consists of 33 members in humans. Although the majority are orphan receptors with unknown functions, many reports have demonstrated critical functions for some members of this family in organogenesis, neurodevelopment, myelination, angiogenesis, and cancer progression. Importantly, mutations in several aGPCRs have been linked to human diseases. The crystal structure of a shared protein domain, the GPCR Autoproteolysis INducing (GAIN) domain, has enabled the discovery of a common signaling mechanism - a tethered agonist - for this class of receptors. A series of recent reports has shed new light on their biological functions and disease relevance. This review focuses on these recent advances in our understanding of aGPCR biology in the nervous system and the untapped potential of aGPCRs as novel therapeutic targets for neurological disease
Recommended from our members
GAIN domain-mediated cleavage is required for activation of G protein-coupled receptor 56 (GPR56) by its natural ligands and a small-molecule agonist.
Adhesion G protein-coupled receptors (aGPCRs) represent a distinct family of GPCRs that regulate several developmental and physiological processes. Most aGPCRs undergo GPCR autoproteolysis-inducing domain-mediated protein cleavage, which produces a cryptic tethered agonist (termed Stachel (stinger)), and cleavage-dependent and -independent aGPCR signaling mechanisms have been described. aGPCR G1 (ADGRG1 or G protein-coupled receptor 56 (GPR56)) has pleiotropic functions in the development of multiple organ systems, which has broad implications for human diseases. To date, two natural GPR56 ligands, collagen III and tissue transglutaminase (TG2), and one small-molecule agonist, 3-α-acetoxydihydrodeoxygedunin (3-α-DOG), have been identified, in addition to a synthetic peptide, P19, that contains seven amino acids of the native Stachel sequence. However, the mechanisms by which these natural and small-molecule agonists signal through GPR56 remain unknown. Here we engineered a noncleavable receptor variant that retains signaling competence via the P19 peptide. We demonstrate that both natural and small-molecule agonists can activate only cleaved GPR56. Interestingly, TG2 required both receptor cleavage and the presence of a matrix protein, laminin, to activate GPR56, whereas collagen III and 3-α-DOG signaled without any cofactors. On the other hand, both TG2/laminin and collagen III activate the receptor by dissociating the N-terminal fragment from its C-terminal fragment, enabling activation by the Stachel sequence, whereas P19 and 3-α-DOG initiate downstream signaling without disengaging the N-terminal fragment from its C-terminal fragment. These findings deepen our understanding of how GPR56 signals via natural ligands, and a small-molecule agonist may be broadly applicable to other aGPCR family members