Coronary veins determine the pattern of sympathetic innervation in the developing heart

Development (Impact Factor: 6.46). 03/2013; 140(7). DOI: 10.1242/dev.087601
Source: PubMed


Anatomical congruence of peripheral nerves and blood vessels is well recognized in a variety of tissues. Their physical proximity and similar branching patterns suggest that the development of these networks might be a coordinated process. Here we show that large diameter coronary veins serve as an intermediate template for distal sympathetic axon extension in the subepicardial layer of the dorsal ventricular wall of the developing mouse heart. Vascular smooth muscle cells (VSMCs) associate with large diameter veins during angiogenesis. In vivo and in vitro experiments demonstrate that these cells mediate extension of sympathetic axons via nerve growth factor (NGF). This association enables topological targeting of axons to final targets such as large diameter coronary arteries in the deeper myocardial layer. As axons extend along veins, arterial VSMCs begin to secrete NGF, which allows axons to reach target cells. We propose a sequential mechanism in which initial axon extension in the subepicardium is governed by transient NGF expression by VSMCs as they are recruited to coronary veins; subsequently, VSMCs in the myocardium begin to express NGF as they are recruited by remodeling arteries, attracting axons toward their final targets. The proposed mechanism underlies a distinct, stereotypical pattern of autonomic innervation that is adapted to the complex tissue structure and physiology of the heart.

4 Reads
  • Source
    • "The communication describes that the stellate ganglia nerves follow venous vessels in a unique manner, and not arteries as expected for sympathetic axons, to reach the developing sino-atrial node and myocardium. This finding echoes and supplements the pioneering work of Mukouyama and colleagues who provided evidence that distal sympathetic axons use, during an intermediate stage of innervation, large diameter coronary veins of the subepicardial area to grow along the dorsal ventricular wall (Nam et al., 2013). The expression of neurotrophins and the secretion of NGF in particular were shown to be primarily involved in this patterning of the developing mouse heart (Hasan, 2013). "

    Frontiers in Cell and Developmental Biology 10/2015; 3:54. DOI:10.3389/fcell.2015.00054
  • Source
    • "The vertebrate heart is innervated during chamber morphogenesis by parasympathetic and sympathetic fibers, which regulate responses of the cardiovascular system to stress. Recent studies indicate that, upon origination from the stellate ganglion, sympathetic nerves are guided along the cardiac surface by neurotrophic signals from developing coronary vascular cells (Nam et al., 2013). We observed extensive innervation of the atrial surface myocardium in adult zebrafish, with less pronounced innervation of the ventricle (Figure 1C, upper panel). "
    [Show abstract] [Hide abstract]
    ABSTRACT: 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. Copyright © 2015 Elsevier Inc. All rights reserved.
    Developmental Cell 08/2015; 34(4). DOI:10.1016/j.devcel.2015.06.017 · 9.71 Impact Factor
  • Source
    • "Wholemount immunostaining for Neurofilament-66 showed major truncation of the neuronal axons innervating Chd7 fl/fl ;Mesp1-Cre hearts (Fig. 4A). Both sympathetic and parasympathetic axons can be seen on the dorsal surface of the heart by E15.0, although they are predominantly sympathetic (Nam et al., 2013). They are derived from NCCs, which migrate to the dorsal aorta, differentiate into neurons and extend axonal projections into the cardiac tissue (Hasan, 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: CHARGE syndrome is caused by spontaneous loss-of-function mutations to the ATP-dependent chromatin remodeller chromodomain-helicase-DNA-binding protein 7 (CHD7). It is characterised by a distinct pattern of congenital anomalies, including cardiovascular malformations. Disruption to the neural crest lineage has previously been emphasised in the etiology of this developmental disorder. We present evidence for an additional requirement for CHD7 activity in the Mesp1-expressing anterior mesoderm during heart development. Conditional ablation of Chd7 in this lineage results in major structural cardiovascular defects akin to those seen in CHARGE patients, as well as a striking loss of cardiac innervation and embryonic lethality. Genome-wide transcriptional analysis identified aberrant expression of key components of the Class 3 Semaphorin and Slit-Robo signalling pathways in Chd7(fl/fl);Mesp1-Cre mutant hearts. CHD7 localises at the Sema3c promoter in vivo, with alteration of the local chromatin structure seen following Chd7 ablation, suggestive of direct transcriptional regulation. Furthermore, we uncover a novel role for CHD7 activity upstream of critical calcium handling genes, and demonstrate an associated functional defect in the ability of cardiomyocytes to undergo excitation-contraction coupling. This work therefore reveals the importance of CHD7 in the cardiogenic mesoderm for multiple processes during cardiovascular development. Copyright © 2015. Published by Elsevier Inc.
    Developmental Biology 06/2015; 89(1). DOI:10.1016/j.ydbio.2015.06.017 · 3.55 Impact Factor
Show more

Similar Publications

We use cookies to give you the best possible experience on ResearchGate. Read our cookies policy to learn more.