Semaphorin Signaling in Cardiovascular Development

Epstein, Jonathan A.; Aghajanian, Haig; Singh, Manvendra K.

doi:10.1016/j.cmet.2014.12.015

Cited by 94 publications

(85 citation statements)

References 117 publications

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“…We demonstrate that the impact of nerves seems to affect both the expression of growth factors as well as the inflammatory response post injury. Owing to the established role of semaphorin signaling in vascular patterning (Epstein et al, 2015), it is not clear whether a vascular mechanism is involved in the regenerative response as well. Interestingly, modulating expression of growth factors as Ngf by cholinergic signaling has been reported following cholinergic denervation in the brain (da Penha Berzaghi et al, 1993; Lapchak et al, 1993), suggesting interplay between cholinergic nerves and Nrg1 and Ngf activity.…”

Section: Discussionmentioning

confidence: 99%

Nerves Regulate Cardiomyocyte Proliferation and Heart Regeneration

et al. 2015

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SUMMARY Some organisms, such as adult zebrafish and newborn mice, have the capacity to regenerate heart tissue following injury. Unraveling the mechanisms of heart regeneration is fundamental to understanding why regeneration fails in adult humans. Numerous studies have revealed that nerves are crucial for organ regeneration, thus we aimed to determine whether nerves guide heart regeneration. Here, we show using transgenic zebrafish that inhibition of cardiac innervation leads to reduction of myocyte proliferation following injury. Specifically, pharmacological inhibition of cholinergic nerve function reduces cardiomyocyte proliferation in the injured hearts of both zebrafish and neonatal mice. Direct mechanical denervation impairs heart regeneration in neonatal mice, which was rescued by the administration of Neuregulin 1 (Nrg1) and Nerve growth factor (Ngf) recombinant proteins. Transcriptional analysis of mechanically denervated hearts revealed a blunted inflammatory and immune response following injury. These findings demonstrate that nerve function is required for both zebrafish and mouse heart regeneration.

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Section: Discussionmentioning

confidence: 99%

Nerves Regulate Cardiomyocyte Proliferation and Heart Regeneration

et al. 2015

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“…1l), Semaphorin and Ephrin–Eph family members involved in cellular motion, axonal guidance and migration were deregulated. Semaphorins play key functions in cardiac morphogenesis and vascular patterning 40,41 . One down-regulated gene, Efnb3 , is associated with the cardiac hypertrophic response in adult heart 42 .…”

Section: Comparative Gene Profilingmentioning

confidence: 99%

Sequential Notch activation regulates ventricular chamber development

et al. 2015

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Ventricular chambers are essential for the rhythmic contraction and relaxation occurring in every heartbeat throughout life. Congenital abnormalities in ventricular chamber formation cause severe human heart defects. How the early trabecular meshwork of myocardial fibres forms and subsequently develops into mature chambers is poorly understood. We show that Notch signalling first connects chamber endocardium and myocardium to sustain trabeculation, and later coordinates ventricular patterning and compaction with coronary vessel development to generate the mature chamber, through a temporal sequence of ligand signalling determined by the glycosyltransferase manic fringe (MFng). Early endocardial expression of MFng promotes Dll4–Notch1 signalling, which induces trabeculation in the developing ventricle. Ventricular maturation and compaction require MFng and Dll4 downregulation in the endocardium, which allows myocardial Jag1 and Jag2 signalling to Notch1 in this tissue. Perturbation of this signalling equilibrium severely disrupts heart chamber formation. Our results open a new research avenue into the pathogenesis of cardiomyopathies.

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“…Afterward, these molecules have been shown to regulate other physiological and pathological processes outside of the nervous system, such as vascular endothelial cell motility, cardiovascular development, lymphocyte activation, bone and lung morphogenesis, cancer angiogenesis and metastatic dissemination 3,6,7,8 . The Sema family is divided into 8 classes accordingly to structural characteristics and organisms of origin: class 1 and 2 are encoded by invertebrates, classes 3–7 are from vertebrates, and class V Sema are found in viruses.…”

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confidence: 99%

Class 3 semaphorins in cardiovascular development

Valdembri

Regano

Maione

et al. 2016

Cell Adhesion & Migration

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Secreted class 3 semaphorins (Sema3), which signal through holoreceptor complexes that are formed by different subunits, such as neuropilins (Nrps), proteoglycans, and plexins, were initially characterized as fundamental regulators of axon guidance during embryogenesis. Subsequently, Sema3A, Sema3C, Sema3D, and Sema3E were discovered to play crucial roles in cardiovascular development, mainly acting through Nrp1 and Plexin D1, which funnels the signal of multiple Sema3 in vascular endothelial cells. Mechanistically, Sema3 proteins control cardiovascular patterning through the enzymatic GTPase-activating-protein activity of the cytodomain of Plexin D1, which negatively regulates the function of Rap1, a small GTPase that is well-known for its ability to drive vascular morphogenesis and to elicit the conformational activation of integrin adhesion receptors.

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Semaphorin Signaling in Cardiovascular Development

Cited by 94 publications

References 117 publications

Nerves Regulate Cardiomyocyte Proliferation and Heart Regeneration

Nerves Regulate Cardiomyocyte Proliferation and Heart Regeneration

Sequential Notch activation regulates ventricular chamber development

Class 3 semaphorins in cardiovascular development

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