Diverse Functions of Retinoic Acid in Brain Vascular Development

Bonney, Stephanie; Harrison-Uy, Susan J.; Mishra, Swati; MacPherson, Amber M.; Choe, Youngshik; Li, Dan; Jaminet, Shou-Ching; Fruttiger, Marcus; Pleasure, Samuel J.; Siegenthaler, Julie A.

doi:10.1523/jneurosci.3952-15.2016

Cited by 37 publications

(58 citation statements)

References 57 publications

(11 reference statements)

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“…However, RA is an established inhibitor of WNT signaling in other cell types through interaction of RA receptors with WNT signaling protein β-catenin (Chanda et al, 2013; Easwaran et al, 1999; Mulholland et al, 2005). Even more convincingly, we recently showed that the same RA signaling mutants used in these studies, Pdgfbi-Cre; dnRAR403-fl/fl, have elevated endothelial WNT signaling at a later developmental time point (Bonney et al, 2016). This, along with our observations about RA treatment on WNT signaling in the PNVP, suggests that RA is a direct inhibitor of endothelial WNT signaling.…”

Section: Discussionmentioning

confidence: 89%

“…Here we show that E14.5 Pdgfbi-Cre; dnRAR403-fl/fl mutants do not have the severe cerebrovascular growth defects observed in Foxc1 mutants but that there is phenotype, namely a significant increase in endothelial cell proliferation. We have found older Pdgfbi-Cre; dnRAR403-fl/fl mutant embryos have enlarged blood vessels and develop small microbleeds (Bonney et al, 2016). Thus, RA acting as an inhibitor of endothelial WNT signaling, plays in important role in vascular morphogenesis.…”

Section: Discussionmentioning

confidence: 91%

“…This idea is based on data that RA suppresses Dkk1 in the developing foregut (Chen et al, 2010) and our own work showing that RA-deficient mutants ( Rdh10 hypomorphs) have elevated soluble WNT inhibitors in the neocortex (Bonney et al, 2016). We used real-time PCR to compare gene expression of WNT inhibitors Dkk1, Sfrp1, Sfrp2, Sfrp4 and Sfrp5 in PNVP/meninges tissue isolated from the telencephalon of control and Foxc1 mutants ± RA exposure.…”

Section: Resultsmentioning

confidence: 99%

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Cerebrovascular defects in Foxc1 mutants correlate with aberrant WNT and VEGF—A pathways downstream of retinoic acid from the meninges

Mishra

Choe

Pleasure

et al. 2016

Developmental Biology

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Growth and maturation of the cerebrovasculature is a vital event in neocortical development however mechanisms that control cerebrovascular development remain poorly understood. Mutations in or deletions that include the FOXC1 gene are associated with congenital cerebrovascular anomalies and increased stroke risk in patients. Foxc1 mutant mice display severe cerebrovascular hemorrhage at late gestational ages. While these data demonstrate Foxc1 is required for cerebrovascular development, its broad expression in the brain vasculature combined with Foxc1 mutant’s complex developmental defects have made it difficult to pinpoint its function(s). Using global and conditional Foxc1 mutants, we find 1) significant cerebrovascular growth defects precede cerebral hemorrhage and 2) expression of Foxc1 in neural crest-derived meninges and brain pericytes, though not endothelial cells, is required for normal cerebrovascular development. We provide evidence that reduced levels of meninges-derived retinoic acid (RA), caused by defects in meninges formation in Foxc1 mutants, is a major contributing factor to the cerebrovascular growth defects in Foxc1 mutants. We provide data that suggests that meninges-derived RA ensures adequate growth of the neocortical vasculature via regulating expression of WNT pathway proteins and neural progenitor derived-VEGF-A. Our findings offer the first evidence for a role of the meninges in brain vascular development and provide new insight into potential causes of cerebrovascular defects in patients with FOXC1 mutations.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 91%

Section: Resultsmentioning

confidence: 99%

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Cerebrovascular defects in Foxc1 mutants correlate with aberrant WNT and VEGF—A pathways downstream of retinoic acid from the meninges

Mishra

Choe

Pleasure

et al. 2016

Developmental Biology

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“…The PNVP overlaying the cerebral cortex and the cerebrovasculature do not develop normally in Foxc1 mutants but these vascular phenotypes are rescued with maternal retinoic acid supplementation, pointing to RA as a key regulator of this process (Mishra, Choe, Pleasure, & Siegenthaler, 2016). Rdh10 mutant embryos have globally reduced RA levels due to reduced activity of Rdh10 needed for the first step in RA synthesis and exhibit a similar, though more severe, cerebrovascular phenotype (Bonney et al, 2016). In the PNVP of Foxc1 and Rdh10 mutants, vessels are hyperplastic and endothelial cell proliferation was elevated (Bonney et al, 2016; Mishra et al, 2016).…”

Section: Retinoic Acid In Organ-specific Vascular Developmentmentioning

confidence: 99%

“…Rdh10 mutant embryos have globally reduced RA levels due to reduced activity of Rdh10 needed for the first step in RA synthesis and exhibit a similar, though more severe, cerebrovascular phenotype (Bonney et al, 2016). In the PNVP of Foxc1 and Rdh10 mutants, vessels are hyperplastic and endothelial cell proliferation was elevated (Bonney et al, 2016; Mishra et al, 2016). The PNVP phenotype in Rdh10 and Foxc1 mutants correlated with reduced endothelial Wnt-β-catenin signaling in the PNVP; in Rdh10 mutants, vessels within the cerebral cortex also had reduced endothelial Wnt-β-catenin signaling (Bonney et al, 2016; Mishra et al, 2016).…”

Section: Retinoic Acid In Organ-specific Vascular Developmentmentioning

confidence: 99%

Retinoic acid signaling in vascular development

Pawlikowski

Wragge

Siegenthaler

2019

Genesis

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Formation of the vasculature is an essential developmental process, delivering oxygen and nutrients to support cellular processes needed for tissue growth and maturation. Retinoic acid (RA) and its downstream signaling pathway is vital for normal pre- and post-natal development, playing key roles in the specification and formation of many organs and tissues. Here we review the role of RA in blood and lymph vascular development, beginning with embryonic yolk sac vasculogenesis and remodeling and discussing RA’s organ-specific roles in angiogenesis and vessel maturation. In particular, we highlight the multi-faceted role of RA signaling in CNS vascular development and acquisition of blood-brain barrier properties.

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Parallels between the Developing Vascular and Neural Systems: Signaling Pathways and Future Perspectives for Regenerative Medicine

2021

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Neurovascular disorders, which involve the vascular and nervous systems, are common. Research on such disorders usually focuses on either vascular or nervous components, without looking at how they interact. Adopting a neurovascular perspective is essential to improve current treatments. Therefore, comparing molecular processes known to be involved in both systems separately can provide insight into promising areas of future research. Since development and regeneration share many mechanisms, comparing signaling molecules involved in both the developing vascular and nervous systems and shedding light to those that they have in common can reveal processes, which have not yet been studied from a regenerative perspective, yet hold great potential. Hence, this review discusses and compares processes involved in the development of the vascular and nervous systems, in order to provide an overview of the molecular mechanisms, which are most promising with regards to treatment for neurovascular disorders. Vascular endothelial growth factor, semaphorins, and ephrins are found to hold the most potential, while fibroblast growth factor, bone morphogenic protein, slits, and sonic hedgehog are shown to participate in both the developing vascular and nervous systems, yet have not been studied at the neurovascular level, therefore being of special interest for future research.

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Diverse Functions of Retinoic Acid in Brain Vascular Development

Cited by 37 publications

References 57 publications

Cerebrovascular defects in Foxc1 mutants correlate with aberrant WNT and VEGF—A pathways downstream of retinoic acid from the meninges

Cerebrovascular defects in Foxc1 mutants correlate with aberrant WNT and VEGF—A pathways downstream of retinoic acid from the meninges

Retinoic acid signaling in vascular development

Parallels between the Developing Vascular and Neural Systems: Signaling Pathways and Future Perspectives for Regenerative Medicine

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