Longitudinal MRI of the developing ferret brain reveals regional variations in timing and rate of growth.

Normative ferret brain development was characterized using magnetic resonance imaging. Brain growth was longitudinally monitored in 10 ferrets (equal numbers of males and females) from postnatal day 8 (P8) through P38 in 6-d increments. Template T2-weighted images were constructed at each age, and these were manually segmented into 12 to 14 brain regions.

Development of a novel Guinea Pig model producing transgenerational endothelial transcriptional changes driven by maternal food restriction and a second metabolic insult of high fat diet.

Developmental programming of chronic adverse cardiovascular health outcomes has been studied both using numerous human populations and an array of animal models. However, the mechanisms that produce transgenerational effects have been difficult to study due to a lack of developmentally relevant models. As such, how increased disease risk is carried to the second generation has been poorly studied.

GPR39 Knockout Worsens Microcirculatory Response to Experimental Stroke in a Sex-Dependent Manner.

No current treatments target microvascular reperfusion after stroke, which can contribute to poor outcomes even after successful clot retrieval. The G protein-coupled receptor GPR39 is expressed in brain peri-capillary pericytes, and has been implicated in microvascular regulation, but its role in stroke is unknown. We tested the hypothesis that GPR39 plays a protective role after stroke, in part due to preservation of microvascular perfusion.

Proteomic profiling of concurrently isolated primary microvascular endothelial cells, pericytes, and vascular smooth muscle cells from adult mouse heart.

The microcirculation serves crucial functions in adult heart, distinct from those carried out by epicardial vessels. Microvessels are governed by unique regulatory mechanisms, impairment of which leads to microvessel-specific pathology. There are few treatment options for patients with microvascular heart disease, primarily due to limited understanding of underlying pathology.

Control of coronary vascular resistance by eicosanoids via a novel GPCR.

Arachidonic acid metabolites epoxyeicosatrienoates (EETs) and hydroxyeicosatetraenoates (HETEs) are important regulators of myocardial blood flow and coronary vascular resistance (CVR), but their mechanisms of action are not fully understood. We applied a chemoproteomics strategy using a clickable photoaffinity probe to identify G protein-coupled receptor 39 (GPR39) as a microvascular smooth muscle cell (mVSMC) receptor selective for two endogenous eicosanoids, 15-HETE and 14,15-EET, which act on the receptor to oppose each other's activity. The former increases mVSMC intracellular calcium via GPR39 and augments coronary microvascular resistance, and the latter inhibits these actions.

Horizontal mtDNA transfer between cells is common during mouse development.

Cells transmit their genomes vertically to daughter cells during cell divisions. Here, we demonstrate the occurrence and extent of horizontal mitochondrial (mt)DNA acquisition between cells that are not in a parent-offspring relationship. Extensive single-cell sequencing from various tissues and organs of adult chimeric mice composed of cells carrying distinct mtDNA haplotypes showed that a substantial fraction of individual cardiomyocytes, neurons, glia, intestinal, and spleen cells captured donor mtDNA at high levels.

(Phospho)Proteomic dataset of ischemia- and ultrasound- stimulated mouse cardiac endothelial cells in vitro.

Cardiac endothelial cells respond to both ischemia and therapeutic ultrasound; the proteomic changes underlying these responses are unknown. This data article provides raw and processed data resulting from our global, unbiased phosphoproteomics investigation conducted on primary mouse cardiac endothelial cells exposed to ischemia (2-hour oxygen glucose deprivation) and ultrasound (250 kHz, 1.2 MPa) in vitro [1].

Role of GPR39 in Neurovascular Homeostasis and Disease.

GPR39, a member of the ghrelin family of G protein-coupled receptors, is zinc-responsive and contributes to the regulation of diverse neurovascular and neurologic functions. Accumulating evidence suggests a role as a homeostatic regulator of neuronal excitability, vascular tone, and the immune response. We review GPR39 structure, function, and signaling, including constitutive activity and biased signaling, and summarize its expression pattern in the central nervous system.

Mapping the Molecular Architecture Required for Lipid-Binding Pockets Using a Subset of Established and Orphan G-Protein Coupled Receptors.

G-protein coupled receptors (GPCRs) sense a wide variety of stimuli, including lipids, and transduce signals to the intracellular environment to exert various physiological responses. However, the structural features of GPCRs responsible for detecting and triggering responses to distinct lipid ligands have only recently begun to be revealed. 14,15-epoxyeicosatrienoic acid (14,15-EET) is one such lipid mediator that plays an essential role in the vascular system, displaying both vasodilatory and anti-inflammatory properties.

Phosphoproteomic response of cardiac endothelial cells to ischemia and ultrasound.

Myocardial infarction and subsequent therapeutic interventions activate numerous intracellular cascades in every constituent cell type of the heart. Endothelial cells produce several protective compounds in response to therapeutic ultrasound, under both normoxic and ischemic conditions. How endothelial cells sense ultrasound and convert it to a beneficial biological response is not known.

Age-dependent transcriptional alterations in cardiac endothelial cells.

Aging is a significant risk factor for cardiovascular disease. Despite the fact that endothelial cells play critical roles in cardiovascular function and disease, the molecular impact of aging on this cell population in many organ systems remains unknown. In this study, we sought to determine age-associated transcriptional alterations in cardiac endothelial cells.

Effect of thermostable mutations on the neurotensin receptor 1 (NTSR) activation state.

Neurotensin (NTS) is a 13-amino acid neuropeptide with neuroendocrine and vasoactive functions that is widely expressed in the central nervous system and gastrointestinal tract. NTS is sensed by a multiple cell surface proteins including two G protein-coupling receptors (GPCRs): NTS receptors 1 and 2 (NTSR and NTSR). Crystal structures of NTSR have successfully elucidated agonist binding within the orthosteric pocket of receptor but have not revealed the full activation state of the receptor.

Neuronal Polarization Packs a One-Two Punch.

In this issue of Neuron, Ambrozkiewicz et al. (2018) define a new molecular circuit controlling neuronal polarization and migration through the transcription factor SOX9 to coordinate the production of regulators of both protein synthesis and degradation.

Endothelial transcriptomics reveals activation of fibrosis-related pathways in hypertension.

Hypertension poses a significant challenge to vasculature homeostasis and stands as the most common cardiovascular disease in the world. Its effects are especially profound on endothelial cells that form the inner lining of the vasculature and are directly exposed to the effects of excess pressure. Here, we characterize the in vivo transcriptomic response of cardiac endothelial cells to hypertension by rapidly isolating these cells from the spontaneous hypertension mouse model BPH/2J and its normotensive BPN/3J control strain and performing and RNA sequencing on both.

Specific gene expression profiles are associated with a pathologic complete response to neoadjuvant therapy in esophageal adenocarcinoma.

Background: Predicting treatment response to chemo-radiotherapy (CRT) in esophageal cancer remains an unrealized goal despite studies linking constellations of genes to prognosis. We aimed to determine if specific expression profiles are associated with pathologic complete response (pCR) after neoadjuvant CRT.

Methods: Eleven genes previously associated with esophageal cancer prognosis were identified.

The START App: a web-based RNAseq analysis and visualization resource.

Summary: Transcriptional profiling using RNA sequencing (RNAseq) has emerged as a powerful methodology to quantify global gene expression patterns in various contexts from single cells to whole tissues. The tremendous amount of data generated by this profiling technology presents a daunting challenge in terms of effectively visualizing and interpreting results. Convenient and intuitive data interfaces are critical for researchers to easily upload, analyze and visualize their RNAseq data.

Functional screening for G protein-coupled receptor targets of 14,15-epoxyeicosatrienoic acid.

Epoxyeicosatrienoic acids (EETs) are potent vasodilators that play important roles in cardiovascular physiology and disease, yet the molecular mechanisms underlying the biological actions of EETs are not fully understood. Multiple lines of evidence suggest that the actions of EETs are in part mediated via G protein-coupled receptor (GPCR) signaling, but the identity of such a receptor has remained elusive. We sought to identify 14,15-EET-responsive GPCRs.

Disrupting Dimerization Translocates Soluble Epoxide Hydrolase to Peroxisomes.

The epoxyeicosatrienoic acid (EET) neutralizing enzyme soluble epoxide hydrolase (sEH) is a neuronal enzyme, which has been localized in both the cytosol and peroxisomes. The molecular basis for its dual localization remains unclear as sEH contains a functional peroxisomal targeting sequence (PTS). Recently, a missense polymorphism was identified in human sEH (R287Q) that enhances its peroxisomal localization.

Brain patterning perturbations following PTEN loss.

This review will consider the impact of compromised PTEN signaling in brain patterning. We approach understanding the contribution of PTEN to nervous system development by surveying the findings from the numerous genetic loss-of-function models that have been generated as well as other forms of PTEN inactivation. By exploring the developmental programs influenced by this central transduction molecule, we can begin to understand the molecular mechanisms that shape the developing brain.

Isl1 directly controls a cholinergic neuronal identity in the developing forebrain and spinal cord by forming cell type-specific complexes.

The establishment of correct neurotransmitter characteristics is an essential step of neuronal fate specification in CNS development. However, very little is known about how a battery of genes involved in the determination of a specific type of chemical-driven neurotransmission is coordinately regulated during vertebrate development. Here, we investigated the gene regulatory networks that specify the cholinergic neuronal fates in the spinal cord and forebrain, specifically, spinal motor neurons (MNs) and forebrain cholinergic neurons (FCNs).

STRAD pseudokinases regulate axogenesis and LKB1 stability.

Background: Neuronal polarization is an essential step of morphogenesis and connectivity in the developing brain. The serine/threonine kinase LKB1 is a key regulator of cell polarity, metabolism, tumorigenesis, and is required for axon formation. It is allosterically regulated by two related and evolutionarily conserved pseudokinases, STe20-Related ADapters (STRADs) α and β.

Cancer- and endotoxin-induced cachexia require intact glucocorticoid signaling in skeletal muscle.

Cachexia is a wasting condition defined by skeletal muscle atrophy in the setting of systemic inflammation. To explore the site at which inflammatory mediators act to produce atrophy in vivo, we utilized mice with a conditional deletion of the inflammatory adaptor protein myeloid differentiation factor 88 (MyD88). Although whole-body MyD88-knockout (wbMyD88KO) mice resist skeletal muscle atrophy in response to LPS, muscle-specific deletion of MyD88 is not protective.

Expression of myeloid differentiation factor 88 in neurons is not requisite for the induction of sickness behavior by interleukin-1β.

Background: Animals respond to inflammation by suppressing normal high-energy activities, including feeding and locomotion, in favor of diverting resources to the immune response. The cytokine interleukin-1 beta (IL-1β) inhibits normal feeding and locomotor activity (LMA) via its actions in the central nervous system (CNS). Behavioral changes in response to IL-1β are mediated by myeloid differentiation factor 88 (MyD88) in non-hematopoietic cells.

An organotypic slice culture model of chronic white matter injury with maturation arrest of oligodendrocyte progenitors.

Background: CNS myelination disturbances commonly occur in chronic white matter lesions in neurodevelopmental and adult neurological disorders. Recent studies support that myelination failure can involve a disrupted cellular repair mechanism where oligodendrocyte (OL) progenitor cells (OPCs) proliferate in lesions with diffuse astrogliosis, but fail to fully differentiate to mature myelinating OLs. There are no in vitro models that reproduce these features of myelination failure.

TGF-beta signaling specifies axons during brain development.

In the mammalian brain, the specification of a single axon and multiple dendrites occurs early in the differentiation of most neuron types. Numerous intracellular signaling events for axon specification have been described in detail. However, the identity of the extracellular factor(s) that initiate neuronal polarity in vivo is unknown.