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Absence of hevin mRNA in monoaminergic nuclei in mouse brain. Hybridization signal for hevin (red) and tyrosine hydroxylase (green) is observed in midbrain monoaminergic nuclei, substantia nigra, ventral tegmental area (a), and locus cœruleus (b). Hybridization signal between hevin (red) and tryptophane hydroxylase (green) is observed in Raphe nuclei (c). No co-localization is observed between hevin-positive cells (arrows) and tyrosine hydroxylase-positive and tryptophane hydroxylase-positive neurons (stars). DAPI signal is also presented (blue staining in the nucleus). The scale bar is 100 µm. See list of abbreviations
Source publication
Hevin, also known as SPARC-like 1, is a member of the secreted protein acidic and rich in cysteine family of matricellular proteins, which has been implicated in neuronal migration and synaptogenesis during development. Unlike previously characterized matricellular proteins, hevin remains strongly expressed in the adult brain in both astrocytes and...
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The basal forebrain (BF) is involved in arousal, attention, and reward processing but the role of individual BF neuronal subtypes is still being uncovered. Glutamatergic neurons are the least well-understood of the three main BF neurotransmitter phenotypes. Here we analyzed the distribution, size, calcium-binding protein content and projections of...
Citations
... 15 In human brains, this protein was also observed. 17,18 Moreover, its expressions by astrocytes were obviously upregulated in rats after transient ischemic stroke. 16 Whether in ischemic stroke or intracerebral hemorrhage rats, SPARCL1 expressions were prominently increased in injured brain tissues. ...
Background
Secreted protein acidic and rich in cysteine-like 1 (SPARCL1) regulates synaptic stability and is up-regulated during axonal regeneration. Here, serum SPARCL1 was determined for estimating severity and prognosticating early neurological deterioration (END) and functional outcomes of acute intracerebral hemorrhage (ICH).
Methods
In this prospective observational cohort study of 156 patients with supratentorial ICH, blood samples of 53 were acquired not only at admission but also ad days 1, 3, 5, 7 and 10. Another group of 53 healthy controls were recruited. The modified Rankin Scale (mRS) scores of 3–6 at poststroke six months were regarded as poor prognosis.
Results
As opposed to controls, serum SPARCL1 levels were markedly elevated during the early ten days after ICH, with the highest levels at days 1 and 3. Admission serum SPARCL1 levels were independently correlated with National Institutes of Health Stroke Scale scores and hematoma volume, were significantly increased in the order of six-month mRS scores from 0 to 6 and were independently correlated with six-month mRS scores. Serum SPARCL1 levels were linearly related to risks of poor six-month prognosis and END under restricted cubic spline, had significant efficiency under receiver operating characteristic (ROC) curve and were independently associated with END and poor prognosis. Subgroup analysis confirmed that no interactions existed for associations of serum SPARCL1 levels with other variables, such as age, gender and some specific vascular risk factors. END and poor prognosis prediction models integrating serum SPARCL1 were displayed using the two nomograms. The poor prognosis prediction model, but END prediction model not, performed well under calibration curve, decision curve and ROC curve.
Conclusion
A substantial elevation of serum SPARCL1 levels during the early period after ICH is independently related to illness severity and poor neurological outcomes, thus signifying that serum SPARCL1 may appear as a prognostic biomarker of ICH.
... FISH was used to determine Cyp19a1-expressing cells, as described previously [18,19]. For the single FISH experiments, every twentieth slide from the series was used for each rat, which corresponds to a section every 240 µm. ...
Background
Aromatase catalyzes the synthesis of estrogens from androgens. Knowledge on its regional expression in the brain is of relevance to the behavioral implications of these hormones that might be linked to sex differences in mental health. The present study investigated the distribution of cells expressing the aromatase coding gene ( Cyp19a1) in limbic regions of young adult rats of both sexes, and characterized the cell types expressing this gene.
Methods
Cyp19a1 mRNA was mapped using fluorescent in situ hybridization (FISH). Co-expression with specific cell markers was assessed with double FISH; glutamatergic, gamma-aminobutyric acid (GABA)-ergic, glial, monoaminergic, as well as interneuron markers were tested. Automated quantification of the cells expressing the different genes was performed using CellProfiler. Sex differences in the number of cells expressing Cyp19a1 was tested non-parametrically, with the effect size indicated by the rank-biserial correlation. FDR correction for multiple testing was applied.
Results
In the male brain, the highest percentage of Cyp19a1 ⁺ cells was found in the medial amygdaloid nucleus and the bed nucleus of stria terminalis, followed by the medial preoptic area, the CA2/3 fields of the hippocampus, the cortical amygdaloid nucleus and the amygdalo-hippocampal area. A lower percentage was detected in the caudate putamen, the nucleus accumbens, and the ventromedial hypothalamus. In females, the distribution of Cyp19a1 ⁺ cells was similar but at a lower percentage. In most regions, the majority of Cyp19a1 ⁺ cells were GABAergic, except for in the cortical-like regions of the amygdala where most were glutamatergic. A smaller fraction of cells co-expressed Slc1a3 , suggesting expression of Cyp19a1 in astrocytes; monoaminergic markers were not co-expressed. Moreover, sex differences were detected regarding the identity of Cyp19a1 ⁺ cells.
Conclusions
Females show overall a lower number of cells expressing Cyp19a1 in the limbic brain. In both sexes, aromatase is expressed in a region-specific manner in GABAergic and glutamatergic neurons. These findings call for investigations of the relevance of sex-specific and region-dependent expression of Cyp19a1 in the limbic brain to sex differences in behavior and mental health.
... Sparc-like protein 1 (Sparcl1), which is also known as Hevin, is a matricellular secreted protein that is predominantly expressed by astrocytes and a subset of neurons in the CNS. Endothelial cells also express Sparcl1 mRNA; however, protein expression by these cells has not been observed 48,49 . Downregulation or missense mutations in SPARCL1/Hevin have been reported in numerous neurological disorders such as autism, schizophrenia, and depression [50][51][52] . ...
Delivering genes to and across the brain vasculature efficiently and specifically across species remains a critical challenge for addressing neurological diseases. We have evolved adeno-associated virus (AAV9) capsids into vectors that transduce brain endothelial cells specifically and efficiently following systemic administration in wild-type mice with diverse genetic backgrounds, and in rats. These AAVs also exhibit superior transduction of the CNS across non-human primates (marmosets and rhesus macaques), and in ex vivo human brain slices, although the endothelial tropism is not conserved across species. The capsid modifications translate from AAV9 to other serotypes such as AAV1 and AAV-DJ, enabling serotype switching for sequential AAV administration in mice. We demonstrate that the endothelial-specific mouse capsids can be used to genetically engineer the blood-brain barrier by transforming the mouse brain vasculature into a functional biofactory. We apply this approach to Hevin knockout mice, where AAV-X1-mediated ectopic expression of the synaptogenic protein Sparcl1/Hevin in brain endothelial cells rescued synaptic deficits.
... Hevin proteina matrizelularra hainbat ehunetan eta zelula motatan adierazten da. Gizakietan, garunean, heste mehar eta lodian, biriketan, gibelean, pankrean eta hestegorrian adierazten da [45][46][47]. Karraskarietan, aldiz, garunean, hestean, pankrean, erretinan, bihotzean, guruin adrenaletan, epididimoan eta biriketan adierazten da, eta maila baxuetan giltzurrunean [12,45,[48][49][50][51][52][53]. Hevin ehun konektiboan eta muskulu eskeletikoan ere adierazten da, non lotune neuromuskularrean baitago [54]. ...
... Gainera, proteina matrizelular gehienak garunaren garapenean adierazten diren bitartean, hevin oso adierazita dago garun helduan [12,49,50,[55][56][57][58]. [46,51]. Gainera, mikroskopia elektronikoak eta irudi fokukideek hevin aurkitu dute sinapsien inguruko prozesu astrozitikoetan, mintz postsinaptikoetan eta karraskari helduen garunaren zirrikitu sinaptiko kitzikagarrietan [12,13,40,49,56,[58][59][60]. ...
... Hevin gizaki helduen LZRan, plasman eta garunean ere de tek ta tzen da, zehazki bekoki aurreko kortexean, buztandun nukleoan, hipokanpoan, zerebeloan, entzefalo-enborrean eta gongoil sentsorialen neuronetan [44,46,[61][62][63][64][65]. Garrantzitsua da sagu eta giza garun helduan egindako ikerketek agerian utzi dutela hevinentzako antzeko zelula-adierazpena bietan [46,57]. ...
Proteina matrizelularrak zelulaz kanpoko matrizeko (ZKM) molekulak dira, zeinek beste ZKMko molekuletatik bereizten dituzten funtzio espezifikoak baitituzte. Adibidez, zelulen funtzioa modulatzen dute eta gaitasun desitsaskorrak dituzte, besteak beste. Azkenengo urteetan, hainbat molekulek proteina matrizelularren ezaugarriak betetzen dituztela ikusi da, eta horien parte-hartzea nabarmenduz joan da gaixotasun neuropsikiatrikoetan. Lan honetan, alde batetik, proteina matrizelularren ezaugarriak eta talde honetako partaide nagusien funtzio garrantzitsuenak azalduko dira. Eta, bestetik, gehiago sakonduko da hevin proteina matrizelularraren funtzioetan, gaixotasun neuropsikiatrikoetan duen inplikazioa aipatuz.
... It is worth mentioning that the increase in FNDC5-BDNF system activity in the periphery is barely adding to the changes in brain BDNF immunoreactivity, because BDNF practically does not penetrate the BBB under healthy physiological conditions (Hernandez et al., 2022). A recent study showed that subcutaneous administration of irisin resulted in an increase of dendrite complexity in the CA1 and CA3 areas of the hippocampus in coincidence with upregulation of mRNA for PGC-1α, FNDC5, and BDNF, therefore, supporting the neurotrophic mechanism of irisin action (Mongrédien et al., 2019). ...
... The discovery of receptors specific to irisin, the integrin family receptor α1β1, and especially, αvβ5 (Kim et al., 2018), strongly confirmed the involvement of astrocytes, since these cells are known to express specifically integrin receptor αvβ5 (Milner et al., 1999). Subcutaneous irisin led to upregulation of mRNA for the astrocyte marker hevin (Mongrédien et al., 2019) and downregulation of tumor growth factor 1 (TGF-β1) mRNA, which would promote neuroplasticity due to respective changes in the release of these astrocyte signaling molecules (Tewari and Majumdar, 2012;Ota et al., 2013;Kim and Leem, 2019). All these remarkable discoveries give a new impulse to study the effects of irisin in the brain using glia as a model of irisin action. ...
Adaptive neuroplasticity is a pivotal mechanism for healthy brain development and maintenance, as well as its restoration in disease- and age-associated decline. Management of mental disorders such as attention deficit hyperactivity disorder (ADHD) needs interventions stimulating adaptive neuroplasticity, beyond conventional psychopharmacological treatments. Physical exercises are proposed for the management of ADHD, and also depression and aging because of evoked brain neuroplasticity. Recent progress in understanding the mechanisms of muscle-brain cross-talk pinpoints the role of the myokine irisin in the mediation of pro-cognitive and antidepressant activity of physical exercises. In this review, we discuss how irisin, which is released in the periphery as well as derived from brain cells, may interact with the mechanisms of cellular autophagy to provide protein recycling and regulation of brain-derived neurotrophic factor (BDNF) signaling via glia-mediated control of BDNF maturation, and, therefore, support neuroplasticity. We propose that the neuroplasticity associated with physical exercises is mediated in part by irisin-triggered autophagy. Since the recent findings give objectives to consider autophagy-stimulating intervention as a prerequisite for successful therapy of psychiatric disorders, irisin appears as a prototypic molecule that can activate autophagy with therapeutic goals.
... Hevin (also known as SPARC-like 1 [SPARCL1], SC1, ECM2 or Mast9) specifically promotes the formation and maintenance of thalamocortical excitatory synapses, by linking presynaptic neurexin-1α and postsynaptic neuroligin-1B [21,22,24,26]. It is highly expressed in human and mouse adult brain [27][28][29][30][31][32], in astrocytes and parvalbumin interneurons and in a restricted number of other neuronal subpopulations, including glutamatergic neurons in cortical and subcortical regions [30]. Importantly, hevin has been implicated in resilience to stress, showing an antidepressant-like effect in a model of social defeat [33]. ...
... Hevin (also known as SPARC-like 1 [SPARCL1], SC1, ECM2 or Mast9) specifically promotes the formation and maintenance of thalamocortical excitatory synapses, by linking presynaptic neurexin-1α and postsynaptic neuroligin-1B [21,22,24,26]. It is highly expressed in human and mouse adult brain [27][28][29][30][31][32], in astrocytes and parvalbumin interneurons and in a restricted number of other neuronal subpopulations, including glutamatergic neurons in cortical and subcortical regions [30]. Importantly, hevin has been implicated in resilience to stress, showing an antidepressant-like effect in a model of social defeat [33]. ...
... Slices were incubated with DAPI (4',6-diamidino-2-fenilindol, D9542, 1:15,000, Sigma-Aldrich, St. Louis, MO, USA) for 20 min at room temperature before mounting with Fluoromount-G. All the slices were scanned on a NanoZoomer 2.0-HT (Hamamatsu Photonics, Hamamatsu City, Japan) for quantification, as previously described [30]. ...
Astrocytic-secreted matricellular proteins have been shown to influence various aspects of synaptic function. More recently, they have been found altered in animal models of psychiatric disorders such as drug addiction. Hevin (also known as Sparc-like 1) is a matricellular protein highly expressed in the adult brain that has been implicated in resilience to stress, suggesting a role in motivated behaviors. To address the possible role of hevin in drug addiction, we quantified its expression in human postmortem brains and in animal models of alcohol abuse. Hevin mRNA and protein expression were analyzed in the postmortem human brain of subjects with an antemortem diagnosis of alcohol use disorder (AUD, n = 25) and controls (n = 25). All the studied brain regions (prefrontal cortex, hippocampus, caudate nucleus and cerebellum) in AUD subjects showed an increase in hevin levels either at mRNA or/and protein levels. To test if this alteration was the result of alcohol exposure or indicative of a susceptibility factor to alcohol consumption, mice were exposed to different regimens of intraperitoneal alcohol administration. Hevin protein expression was increased in the nucleus accumbens after withdrawal followed by a ethanol challenge. The role of hevin in AUD was determined using an RNA interference strategy to downregulate hevin expression in nucleus accumbens astrocytes, which led to increased ethanol consumption. Additionally, ethanol challenge after withdrawal increased hevin levels in blood plasma. Altogether, these results support a novel role for hevin in the neurobiology of AUD.
... The final molecule we explored was Hevin, a synaptogenic extracellular matrix protein (Cahoy et al., 2008;Eroglu, 2009). Although neurons also generate this molecule, in other regions of the rodent visual system such as superior colliculus, Hevin is largely generated by astrocytes (Kucukdereli et al., 2011;Mongrédien et al., 2019). The distribution of Hevin + cells in visual thalamus was strikingly different than the distribution of Fgfr3 + , Gja1 + , Aldh1l1 + , SOX9 + , and S100β + cells, especially in vLGN. ...
The rodent visual thalamus has served as a powerful model to elucidate the cellular and molecular mechanisms that underlie sensory circuit formation and function. Despite significant advances in our understanding of the role of axon-target interactions and neural activity in orchestrating circuit formation in visual thalamus, the role of non-neuronal cells, such as astrocytes, is less clear. In fact, we know little about the transcriptional identity and development of astrocytes in mouse visual thalamus. To address this gap in knowledge, we studied the expression of canonical astrocyte molecules in visual thalamus using immunostaining, in situ hybridization, and reporter lines. While our data suggests some level of heterogeneity of astrocytes in different nuclei of the visual thalamus, the majority of thalamic astrocytes appeared to be labelled in Aldh1l1-EGFP mice. This led us to use this transgenic line to characterize the neonatal and postnatal development of these cells in visual thalamus. Our data show that not only have the entire cohort of astrocytes migrated into visual thalamus by eye-opening but they also have acquired their adult-like morphology, even while retinogeniculate synapses are still maturing. Furthermore, ultrastructural, immunohistochemical, and functional approaches revealed that by eye-opening, thalamic astrocytes ensheath retinogeniculate synapses and are capable of efficient uptake of glutamate. Taken together, our results reveal that the morphological, anatomical, and functional development of astrocytes in visual thalamus occurs prior to eye-opening and the emergence of experience-dependent visual activity.
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... Whereas most of the matricellular proteins are expressed mostly during brain development, hevin remains highly expressed in adult brain (Eroglu, 2009;Lively et al., 2007;Lloyd-Burton & Roskams, 2012;Weaver et al., 2011). Recently, we identified hevin cellular expression profile in adult human brain, specifically in astrocytes and in various types of neurons, in particular in GABAergic parvalbumin-positive neurons, as well as other GABAergic neuronal subtypes and some glutamatergic neurons (Mongrédien et al., 2019). The systematic comparison between mouse and human adult brain revealed a conserved cellular expression pattern for hevin (Mongrédien et al., 2019;Weaver et al., 2011). ...
... Recently, we identified hevin cellular expression profile in adult human brain, specifically in astrocytes and in various types of neurons, in particular in GABAergic parvalbumin-positive neurons, as well as other GABAergic neuronal subtypes and some glutamatergic neurons (Mongrédien et al., 2019). The systematic comparison between mouse and human adult brain revealed a conserved cellular expression pattern for hevin (Mongrédien et al., 2019;Weaver et al., 2011). Hevin is found in all mouse brain regions by virtue of its astrocytic expression and has been observed in every human brain region studied so far including prefrontal cortex, caudate nucleus, brainstem and sensory ganglion neurons (Hashimoto et al., 2016;Mongrédien et al., 2019). ...
... The systematic comparison between mouse and human adult brain revealed a conserved cellular expression pattern for hevin (Mongrédien et al., 2019;Weaver et al., 2011). Hevin is found in all mouse brain regions by virtue of its astrocytic expression and has been observed in every human brain region studied so far including prefrontal cortex, caudate nucleus, brainstem and sensory ganglion neurons (Hashimoto et al., 2016;Mongrédien et al., 2019). Its physiological role in adult brain has been investigated mainly in animal models of brain diseases such as brain injury, ischemic infarction and epilepsy. ...
Hevin is a matricellular glycoprotein that plays important roles in neural developmental processes such as neuronal migration, synaptogenesis and synaptic plasticity. In contrast to other matricellular proteins whose expression decreases when development is complete, hevin remains highly expressed, suggesting its involvement in adult brain function. In vitro studies have shown that hevin can have different post-translational modifications. However, the glycosylation pattern of hevin in the human brain remains unknown, as well as its relative distribution and localization. The present study provides the first thorough characterization of hevin protein expression by western blot in postmortem adult human brain. Our results demonstrated two major specific immunoreactive bands for hevin: an intense band migrating around 130 kDa, and a band migrating around 100 kDa. Biochemical assays revealed that both hevin bands have a different glycosylation pattern. Subcellular fractionation showed greater expression in membrane-enriched fraction than in cytosolic preparation, and a higher expression in prefrontal cortex compared to hippocampus, caudate nucleus and cerebellum. We confirmed that ADAMTS4 and MMP-3 proteases digestion led to an intense double band with similar molecular weight to that described as SPARC-like fragment. Finally, hevin immunoreactivity was also detected in human astrocytoma, meningioma, cerebrospinal fluid and serum samples, but was absent from any blood cell type.
... Hevin protein is a matricellular protein, which, in contrast to most matricellular proteins that are expressed only during the brain development, remains expressed at high levels in the adult brain [1] . Hevin is expressed both in astrocytes and neurons [2] , regulates synaptic plasticity and mediates resilience in animal models of depression [3] . Our preliminary studies show that hevin downregulation modifies the rewarding properties of ethanol. ...
... Throughout postnatal development, hevin is abundantly expressed in astrocytes and in subsets of projection neurons, escalating to high levels during a peak period of synaptic remodeling (Lively and Brown, 2008a;Lloyd-Burton and Roskams, 2012;Mendis et al., 1996;Risher et al., 2014). However, hevin is also strongly expressed in many regions in adult brain in most astrocytes, and also in select populations of inhibitory and excitatory neurons (Hashimoto et al., 2016;Lively et al., 2007;Lloyd-Burton and Roskams, 2012;Mendis et al., 1996;Mongré dien et al., 2019;Risher et al., 2014). Like hevin, SPARC is broadly expressed during development in glial cells and radial glia (progenitor cells that additionally function as guide cells along which neurons migrate) (Vincent et al., 2008), but in adult CNS, SPARC is expressed only in very limited regions by astrocytes and microglia but not neurons (Lloyd-Burton and Roskams, 2012;Mendis et al., 1995;Mongré dien et al., 2019;Vincent et al., 2008). ...
... However, hevin is also strongly expressed in many regions in adult brain in most astrocytes, and also in select populations of inhibitory and excitatory neurons (Hashimoto et al., 2016;Lively et al., 2007;Lloyd-Burton and Roskams, 2012;Mendis et al., 1996;Mongré dien et al., 2019;Risher et al., 2014). Like hevin, SPARC is broadly expressed during development in glial cells and radial glia (progenitor cells that additionally function as guide cells along which neurons migrate) (Vincent et al., 2008), but in adult CNS, SPARC is expressed only in very limited regions by astrocytes and microglia but not neurons (Lloyd-Burton and Roskams, 2012;Mendis et al., 1995;Mongré dien et al., 2019;Vincent et al., 2008). Given the high sequence identity, the striking biological differences between hevin and SPARC remain puzzling, especially as they also seem to share certain functions, as described above, and this dichotomy is important given the characteristic temporal and spatial expression patterns of hevin and SPARC. ...
... While hevin has a well-described role at excitatory synapses, where it encounters NLGN1 (Kucukdereli et al., 2011;Lively and Brown, 2008b;Risher et al., 2014;Singh et al., 2016), it also binds NLGN2, which is found exclusively at inhibitory synapses. Hevin is expressed not only in glial cells but also by select inhibitory as well as excitatory neurons, so that hevin may strategically influence not only excitatory but also inhibitory synapse formation in select neural circuits (Mongré dien et al., 2019). Therefore, taken together, the impact of hevin on neurexin-neuroligin transsynaptic bridges in vivo could be 2-fold: (1) it could adhere neurexins and neuroligins together and (2) it could counteract the inhibitory effect of MDGAs, which are negative regulators of neurexin-neuroligin interaction. ...
Hevin is secreted by astrocytes and its synaptogenic effects are antagonized by the related protein, SPARC. Hevin stabilizes neurexin-neuroligin transsynaptic bridges in vivo. A third protein, membrane-tethered MDGA, blocks these bridges. Here, we reveal the molecular underpinnings of a regulatory network formed by this trio of proteins. The hevin FS-EC structure differs from SPARC, in that the EC domain appears rearranged around a conserved core. The FS domain is structurally conserved and it houses nanomolar affinity binding sites for neurexin and neuroligin. SPARC also binds neurexin and neuroligin, competing with hevin, so its antagonist action is rooted in its shortened N-terminal region. Strikingly, the hevin FS domain competes with MDGA for an overlapping binding site on neuroligin, while the hevin EC domain binds the extracellular matrix protein collagen (like SPARC), so that this trio of proteins can regulate neurexin-neuroligin transsynaptic bridges and also extracellular matrix interactions, impacting synapse formation and ultimately neural circuits.
