Fine-Tuning of Sox17 and Canonical Wnt Coordinates the Permeability Properties of the Blood-Brain Barrier

Corada, Monica; Orsenigo, Fabrizio; Bhat, Ganesh; Conze, Lei Liu; Breviario, Ferruccio; Cunha, Sara I.; Claesson‐Welsh, Lena; Beznoussenko, Galina V.; Mirоnоv, Alexander A.; Bacigaluppi, Marco; Martino, Gianvito; Pitulescu, Mara E.; Adams, Ralf H.; Magnusson, Peetra U.; Dejana, Elisabetta

doi:10.1161/circresaha.118.313316

Cited by 77 publications

(79 citation statements)

References 31 publications

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“…While these factors and their direct responders LRP5 and LRP6 are significantly reduced in the acute phase, they show an induction 7 days after tMCAO. This finding is of special interest as Wnt/β-catenin signaling has recently been shown to conduct its crucial role in brain angiogenesis and BBB formation at the NVU (Liebner et al, 2008;Reis et al, 2012) potentially via SOX17 induction (Corada et al, 2018). Furthermore, pharmacological induction of β-Catenin by CHIR99021 was able to reactivate matured cardiomyocytes and therefore suggested as a future approach for regeneration after myocardial infarction (Fan et al, 2018).…”

Section: Discussionmentioning

confidence: 93%

Gene Expression Dynamics at the Neurovascular Unit During Early Regeneration After Cerebral Ischemia/Reperfusion Injury in Mice

et al. 2020

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With increasing distribution of endovascular stroke therapies, transient middle cerebral artery occlusion (tMCAO) in mice now more than ever depicts a relevant patient population with recanalized M1 occlusion. In this case, the desired therapeutic effect of blood flow restauration is accompanied by breakdown of the blood-brain barrier (BBB) and secondary reperfusion injury. The aim of this study was to elucidate short and intermediate-term transcriptional patterns and the involved pathways covering the different cellular players at the neurovascular unit after transient large vessel occlusion. To achieve this, male C57Bl/6J mice were treated according to an intensive post-stroke care protocol after 60 min occlusion of the middle cerebral artery or sham surgery to allow a high survival rate. After 24 h or 7 days, RNA from microvessel fragments from the ipsilateral and the contralateral hemispheres was isolated and used for mRNA sequencing. Bioinformatic analyses allowed us to depict gene expression changes at two timepoints of neurovascular post-stroke injury and regeneration. We validated our dataset by quantitative real time PCR of BBB-associated targets with well-characterized post-stroke dynamics. Hence, this study provides a well-controlled transcriptome dataset of a translationally relevant mouse model 24 h and 7 days after stroke which might help to discover future therapeutic targets in cerebral ischemia/reperfusion injury.

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Section: Discussionmentioning

confidence: 93%

Gene Expression Dynamics at the Neurovascular Unit During Early Regeneration After Cerebral Ischemia/Reperfusion Injury in Mice

et al. 2020

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“…Moreover, noncanonical Wnt signaling may contribute to the establishment of the BBB phenotype (Pinzón-Daza et al, 2014). Sox17 has been identified as a major target of the β-catenin pathway in endothelial cells (Corada et al, 2019), together with Lef1 and Ets1 (Roudnicky et al, 2020). These Wnt-regulated transcription factors up-regulate the transcription of several junctional proteins, including VE-cadherin and claudin-5 (Roudnicky et al, 2020), possibly involved in the repair of the BSCB.…”

Section: Discussionmentioning

confidence: 99%

Multiplexed chemogenetics in astrocytes and motoneurons restore blood–spinal cord barrier in ALS

et al. 2020

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Blood–spinal cord barrier (BSCB) disruption is thought to contribute to motoneuron (MN) loss in amyotrophic lateral sclerosis (ALS). It is currently unclear whether impairment of the BSCB is the cause or consequence of MN dysfunction and whether its restoration may be directly beneficial. We revealed that SOD1G93A, FUSΔNLS, TDP43G298S, and Tbk1+/− ALS mouse models commonly shared alterations in the BSCB, unrelated to motoneuron loss. We exploit PSAM/PSEM chemogenetics in SOD1G93A mice to demonstrate that the BSCB is rescued by increased MN firing, whereas inactivation worsens it. Moreover, we use DREADD chemogenetics, alone or in multiplexed form, to show that activation of Gi signaling in astrocytes restores BSCB integrity, independently of MN firing, with no effect on MN disease markers and dissociating them from BSCB disruption. We show that astrocytic levels of the BSCB stabilizers Wnt7a and Wnt5a are decreased in SOD1G93A mice and strongly enhanced by Gi signaling, although further decreased by MN inactivation. Thus, we demonstrate that BSCB impairment follows MN dysfunction in ALS pathogenesis but can be reversed by Gi-induced expression of astrocytic Wnt5a/7a.

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“…Forebrain angiogenesis in the mouse was traditionally thought to begin at E10.0-E11.5, to peak around birth and then to gradually decline until postnatal day 25 (P25) when the vascular network becomes functionally mature and quiescent (reviewed by Engelhardt and Liebner, 2014). However, recent RNA sequencing studies suggest the existence of a second wave of postnatal brain angiogenesis that has not been appreciated in previous studies (Corada et al, 2019;Hupe et al, 2017). These studies have shown that endothelial cell-specific mRNA transcripts encoding:…”

Section: Bbb/brb Integrity Depends On Proper Nvu Assembly and Organizmentioning

confidence: 99%

“…(3) cell proliferation markers; or (4) cell cycle markers are decreased between E15.5 and E18.5 in the forebrain when compared with E11.5-E13.5, but exhibit a rapid increase in levels during the first week after birth (P5 and P9), indicative of a potential second wave of angiogenesis (Corada et al, 2019;Hupe et al, 2017). These molecular studies are supported by analyses of endothelial cell proliferation (e.g.…”

Section: Bbb/brb Integrity Depends On Proper Nvu Assembly and Organizmentioning

confidence: 99%

Neuronal and glial regulation of CNS angiogenesis and barriergenesis

2020

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Neurovascular pathologies of the central nervous system (CNS), which are associated with barrier dysfunction, are leading causes of death and disability. The roles that neuronal and glial progenitors and mature cells play in CNS angiogenesis and neurovascular barrier maturation have been elucidated in recent years. Yet how neuronal activity influences these processes remains largely unexplored. Here, we discuss our current understanding of how neuronal and glial development affects CNS angiogenesis and barriergenesis, and outline future directions to elucidate how neuronal activity might influence these processes. An understanding of these mechanisms is crucial for developing new interventions to treat neurovascular pathologies.

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Fine-Tuning of Sox17 and Canonical Wnt Coordinates the Permeability Properties of the Blood-Brain Barrier

Abstract: Supplemental Digital Content is available in the text.

Cited by 77 publications

References 31 publications

Gene Expression Dynamics at the Neurovascular Unit During Early Regeneration After Cerebral Ischemia/Reperfusion Injury in Mice

Gene Expression Dynamics at the Neurovascular Unit During Early Regeneration After Cerebral Ischemia/Reperfusion Injury in Mice

Multiplexed chemogenetics in astrocytes and motoneurons restore blood–spinal cord barrier in ALS

Neuronal and glial regulation of CNS angiogenesis and barriergenesis

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