Microglia regulate GABAergic neurogenesis in prenatal human brain through IGF1.

GABAergic neurons are an essential cellular component of neural circuits. Their abundance and diversity have enlarged significantly in the human brain, contributing to the expanded cognitive capacity of humans. However, the developmental mechanism of the extended production of GABAergic neurons in the human brain remains elusive.

Loss of cardiomyocyte-specific adhesion G-protein-coupled receptor G1 (ADGRG1/GPR56) promotes pressure overload-induced heart failure.

Adhesion G-protein-coupled receptors (AGPCRs), containing large N-terminal ligand-binding domains for environmental mechano-sensing, have been increasingly recognized to play important roles in numerous physiologic and pathologic processes. However, their impact on the heart, which undergoes dynamic mechanical alterations in healthy and failing states, remains understudied. ADGRG1 (formerly known as GPR56) is widely expressed, including in skeletal muscle where it was previously shown to mediate mechanical overload-induced muscle hypertrophy; thus, we hypothesized that it could impact the development of cardiac dysfunction and remodeling in response to pressure overload.

Assessing for prenatal risk factors associated with infant neurologic morbidity using a multivariate analysis.

Objective: To characterize the biochemical and demographic profiles of pregnant people with maternal immune activation (MIA) and identify the prenatal characteristics associated with neurologic morbidity in offspring.

Study Design: This was a retrospective cohort study of 602 mother-infant dyads with births between 2009 and 2010 in California. Multivariable logistic regression was used to build a MIA vulnerability profile including mid-pregnancy biochemical markers and maternal demographic characteristics, and its relationship with infant neurologic morbidity was examined.

Cytokine responses to SARS-COV2 infection in mother-infant dyads: a systematic review and meta-analysis.

Background: The COVID-19 pandemic has affected a significant number of pregnant women worldwide, but studies on immune responses have presented conflicting results. This study aims to systematically review cytokine profiles in pregnant women with SARS-CoV-2 infection and their infants to evaluate immune responses and potential transplacental transfer of cytokines.

Materials And Methods: A comprehensive search of 4 databases was conducted to identify relevant studies.

A cross-species proteomic map reveals neoteny of human synapse development.

The molecular mechanisms and evolutionary changes accompanying synapse development are still poorly understood. Here we generate a cross-species proteomic map of synapse development in the human, macaque and mouse neocortex. By tracking the changes of more than 1,000 postsynaptic density (PSD) proteins from midgestation to young adulthood, we find that PSD maturation in humans separates into three major phases that are dominated by distinct pathways.

Collagen VI Is a Gi-Biased Ligand of the Adhesion GPCR GPR126/ADGRG6.

GPR126/ADGRG6, a member of the adhesion G-protein-coupled receptor family, balances cell differentiation and proliferation through fine-tuning of intracellular cAMP levels, which is achieved through coupling to Gs and Gi proteins. While GPR126-mediated cAMP increase has been proven to be essential for differentiation of Schwann cells, adipocytes and osteoblasts, Gi-signaling of the receptor was found to propagate breast cancer cell proliferation. Extracellular ligands or mechanical forces can modulate GPR126 activity but require an intact encrypted agonist sequence, coined the .

GPR56 S4 variant is required for microglia-mediated synaptic pruning.

ADGRG1 (also called GPR56) plays critical roles in brain development and wiring, including cortical lamination, central nervous system (CNS) myelination, and developmental synaptic refinement. However, the underlying mechanism(s) in mediating such diverse functions is not fully understood. Here, we investigate the function of one specific alternative splicing isoform, the GPR56 splice variant 4 (S4), to test the hypothesis that alternative splicing variants of GPR56 in part support its different functions.

Microglial GPR56 is the molecular target of maternal immune activation-induced parvalbumin-positive interneuron deficits.

Parvalbumin-positive (PV) interneurons play a critical role in maintaining circuit rhythm in the brain, and their reduction is implicated in autism spectrum disorders. Animal studies demonstrate that maternal immune activation (MIA) leads to reduced PV interneurons in the somatosensory cortex and autism-like behaviors. However, the underlying molecular mechanisms remain largely unknown.

Oligodendrocyte Development and Implication in Perinatal White Matter Injury.

Perinatal white matter injury (WMI) is the most common brain injury in premature infants and can lead to life-long neurological deficits such as cerebral palsy. Preterm birth is typically accompanied by inflammation and hypoxic-ischemic events. Such perinatal insults negatively impact maturation of oligodendrocytes (OLs) and cause myelination failure.

The Inhibitory Receptor GPR56 () Is Specifically Expressed by Tissue-Resident Memory T Cells in Mice But Dispensable for Their Differentiation and Function In Vivo.

Tissue-resident memory T (T) cells with potent antiviral and antibacterial functions protect the epithelial and mucosal surfaces of our bodies against infection with pathogens. The strong proinflammatory activities of T cells suggest requirement for expression of inhibitory molecules to restrain these memory T cells under steady state conditions. We previously identified the adhesion G protein-coupled receptor GPR56 as an inhibitory receptor of human cytotoxic lymphocytes that regulates their cytotoxic effector functions.

The association of COVID-19 infection in pregnancy with preterm birth: A retrospective cohort study in California.

Introduction: Our understanding of the association between coronavirus disease 19 (COVID-19) and preterm or early term birth among racially and ethnically diverse populations and people with chronic medical conditions is limited.

Methods: We determined the association between COVID-19 and preterm (PTB) birth among live births documented by California Vital Statistics birth certificates between July 2020 and January 2021 (n=240,147). We used best obstetric estimate of gestational age to classify births as very preterm (VPTB, <32 weeks), PTB (< 37 weeks), early term (37 and 38 weeks), and term (39-44 weeks), as each confer independent risks to infant health and development.

Phospholipid-flippase chaperone CDC50A is required for synapse maintenance by regulating phosphatidylserine exposure.

Synaptic refinement is a critical physiological process that removes excess synapses to establish and maintain functional neuronal circuits. Recent studies have shown that focal exposure of phosphatidylserine (PS) on synapses acts as an "eat me" signal to mediate synaptic pruning. However, the molecular mechanism underlying PS externalization at synapses remains elusive.

Human microglia states are conserved across experimental models and regulate neural stem cell responses in chimeric organoids.

Microglia are resident macrophages in the brain that emerge in early development and respond to the local environment by altering their molecular and phenotypic states. Fundamental questions about microglia diversity and function during development remain unanswered because we lack experimental strategies to interrogate their interactions with other cell types and responses to perturbations ex vivo. We compared human microglia states across culture models, including cultured primary and pluripotent stem cell-derived microglia.

Association of Maternal Immune Activation during Pregnancy and Neurologic Outcomes in Offspring.

Objective: To evaluate neurologic morbidity among offspring during their first year of life in association with prenatal maternal immune activation (MIA), using an inclusive definition.

Study Design: This retrospective cohort study included singletons born in California between 2011 and 2017. MIA was defined by International Classification of Diseases diagnosis of infection, autoimmune disorder, allergy, asthma, atherosclerosis, or malignancy during pregnancy.

Unexpected redundancy of Gpr56 and Gpr97 during hematopoietic cell development and differentiation.

Integrated molecular signals regulate cell fate decisions in the embryonic aortic endothelium to drive hematopoietic stem cell (HSC) generation during development. The G-protein-coupled receptor 56 (Gpr56, also called Adgrg1) is the most highly upregulated receptor gene in cells that take on hematopoietic fate and is expressed by adult bone marrow HSCs. Despite the requirement for Gpr56 in hematopoietic stem/progenitor cell (HS/PC) generation in zebrafish embryos and the highly upregulated expression of GPR56 in treatment-resistant leukemic patients, its function in normal mammalian hematopoiesis remains unclear.

GPR56/ADGRG1 is a platelet collagen-responsive GPCR and hemostatic sensor of shear force.

Circulating platelets roll along exposed collagen at vessel injury sites and respond with filipodia protrusion, shape change, and surface area expansion to facilitate platelet adhesion and plug formation. Various glycoproteins were considered to be both collagen responders and mediators of platelet adhesion, yet the signaling kinetics emanating from these receptors do not fully account for the rapid platelet cytoskeletal changes that occur in blood flow. We found the free N-terminal fragment of the adhesion G protein-coupled receptor (GPCR) GPR56 in human plasma and report that GPR56 is the platelet receptor that transduces signals from collagen and blood flow-induced shear force to activate G protein 13 signaling for platelet shape change.

Cell type-specific evaluation of ADGRG1/GPR56 function in developmental central nervous system myelination.

Myelination of axons in the central nervous system (CNS) is a concerted effort between many cell types, resulting in significant cross-talk and communication among cells. Adhesion G protein-coupled receptor ADGRG1 (GPR56) is expressed in all major glial cells and regulates a wide variety of physiological processes by mediating cell-cell and cell-matrix communications. Previous literature has demonstrated the requirement of ADGRG1 in oligodendrocyte precursor cells (OPCs) during developmental myelination.

A splicing isoform of GPR56 mediates microglial synaptic refinement via phosphatidylserine binding.

Developmental synaptic remodeling is important for the formation of precise neural circuitry, and its disruption has been linked to neurodevelopmental disorders such as autism and schizophrenia. Microglia prune synapses, but integration of this synapse pruning with overlapping and concurrent neurodevelopmental processes, remains elusive. Adhesion G protein-coupled receptor ADGRG1/GPR56 controls multiple aspects of brain development in a cell type-specific manner: In neural progenitor cells, GPR56 regulates cortical lamination, whereas in oligodendrocyte progenitor cells, GPR56 controls developmental myelination and myelin repair.

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.

The expanding functional roles and signaling mechanisms of adhesion G protein-coupled receptors.

The adhesion class of G protein-coupled receptors (GPCRs) is the second largest family of GPCRs (33 members in humans). Adhesion GPCRs (aGPCRs) are defined by a large extracellular N-terminal region that is linked to a C-terminal seven transmembrane (7TM) domain via a GPCR-autoproteolysis inducing (GAIN) domain containing a GPCR proteolytic site (GPS). Most aGPCRs undergo autoproteolysis at the GPS motif, but the cleaved fragments stay closely associated, with the N-terminal fragment (NTF) bound to the 7TM of the C-terminal fragment (CTF).

Long noncoding RNAs interact with mRNAs: A new perspective on the mechanism of premature brain injury.

The molecular mechanism of premature brain injury induced by inflammation is not fully understood. Long noncoding RNAs (lncRNAs) have been reported to play crucial roles in neurological disorders including brain injury. However, little is known about the regulatory function of lncRNAs in the premature brain.

Overlap of polymicrogyria, hydrocephalus, and Joubert syndrome in a family with novel truncating mutations in ADGRG1/GPR56 and KIAA0556.

Genetic mutations associated with brain malformations can lead to a spectrum of severity and it is often difficult to determine whether there are additional pathogenic variants contributing to the phenotype. Here, we present a family affected by a severe brain malformation including bilateral polymicrogyria, hydrocephalus, patchy white matter signal changes, and cerebellar and pontine hypoplasia with elongated cerebellar peduncles leading to the molar tooth sign. While the malformation is reminiscent of bilateral frontoparietal polymicrogyria (BFPP), the phenotype is more severe than previously reported and also includes features of Joubert syndrome (JBTS).

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.