title: Axon guidance of sympathetic neurons to cardiomyocytes by glial cell line-derived neurotrophic factor (GDNF).
abstract: Molecular signaling of cardiac autonomic innervation is an unresolved issue. Here, we show that glial cell line-derived neurotrophic factor (GDNF) promotes cardiac sympathetic innervation in vitro and in vivo. In vitro, ventricular myocytes (VMs) and sympathetic neurons (SNs) isolated from neonatal rat ventricles and superior cervical ganglia were cultured at a close distance. Then, morphological and functional coupling between SNs and VMs was assessed in response to GDNF (10 ng/ml) or nerve growth factor (50 ng/ml). As a result, fractions of neurofilament-M-positive axons and synapsin-I-positive area over the surface of VMs were markedly increased with GDNF by 9-fold and 25-fold, respectively, compared to control without neurotrophic factors. Pre- and post-synaptic stimulation of β1-adrenergic receptors (BAR) with nicotine and noradrenaline, respectively, resulted in an increase of the spontaneous beating rate of VMs co-cultured with SNs in the presence of GDNF. GDNF overexpressing VMs by adenovirus vector (AdGDNF-VMs) attracted more axons from SNs compared with mock-transfected VMs. In vivo, axon outgrowth toward the denervated myocardium in adult rat hearts after cryoinjury was also enhanced significantly by adenovirus-mediated GDNF overexpression. GDNF acts as a potent chemoattractant for sympathetic innervation of ventricular myocytes, and is a promising molecular target for regulation of cardiac function in diseased hearts.
authors.affiliation: Department of Cardiovascular Research, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Miwa
authors.forename: Jong-Kook
authors.initials: JK
authors.lastname: Lee
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Takagishi
authors.forename: Tobias
authors.initials: T
authors.lastname: Opthof
authors.forename: Xianming
authors.initials: X
authors.lastname: Fu
authors.forename: Masumi
authors.initials: M
authors.lastname: Hirabayashi
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Watabe
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Jimbo
authors.forename: Itsuo
authors.initials: I
authors.lastname: Kodama
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
mesh_terms: D000818:Animals; D017763:Autonomic Denervation; D001369:Axons / Q000187:drug effects* / Q000378:metabolism; D018920:Coculture Techniques; D056966:Excitation Contraction Coupling / Q000502:physiology; D005728:Ganglia, Sympathetic / Q000187:drug effects* / Q000378:metabolism; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D032383:Myocytes, Cardiac / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000494:pharmacology; D009469:Neuromuscular Junction / Q000378:metabolism / Q000648:ultrastructure; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism; D017779:Sympathetic Fibers, Postganglionic / Q000187:drug effects* / Q000254:growth & development*
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor; D018342:Receptors, Adrenergic, beta-1; D020932:Nerve Growth Factor