title: Qualitative and quantitative re-evaluation of epidermal growth factor-ErbB1 action on developing midbrain dopaminergic neurons in vivo and in vitro: target-derived neurotrophic signaling (Part 1).
abstract: Although epidermal growth factor (EGF) receptor (ErbB1) is implicated in Parkinson's disease and schizophrenia, the neurotrophic action of ErbB1 ligands on nigral dopaminergic neurons remains controversial. Here, we ascertained colocalization of ErbB1 and tyrosine hydroxylase (TH) immunoreactivity and then characterized the neurotrophic effects of ErbB1 ligands on this cell population. In mesencephalic culture, EGF and glial-derived neurotrophic factor (GDNF) similarly promoted survival and neurite elongation of dopaminergic neurons and dopamine uptake. The EGF-promoted dopamine uptake was not inhibited by GDNF-neutralizing antibody or TrkB-Fc, whereas EGF-neutralizing antibody fully blocked the neurotrophic activity of the conditioned medium that was prepared from EGF-stimulated mesencephalic cultures. The neurotrophic action of EGF was abolished by ErbB1 inhibitors and genetic disruption of erbB1 in culture. In vivo administration of ErbB1 inhibitors to rat neonates diminished TH and dopamine transporter (DAT) levels in the striatum and globus pallidus but not in the frontal cortex. In parallel, there was a reduction in the density of dopaminergic varicosities exhibiting intense TH immunoreactivity. In agreement, postnatal erbB1-deficient mice exhibited similar decreases in TH levels. Although neurotrophic supports to dopaminergic neurons are redundant, these results confirm that ErbB1 ligands contribute to the phenotypic and functional development of nigral dopaminergic neurons.
authors.affiliation: Molecular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Yingjun
authors.initials: Y
authors.lastname: Zheng
authors.forename: Maria
authors.initials: M
authors.lastname: Sibilia
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Abe
authors.forename: Ying-Shan
authors.initials: YS
authors.lastname: Piao
authors.forename: Daisaku
authors.initials: D
authors.lastname: Yokomaku
authors.forename: Ran
authors.initials: R
authors.lastname: Wang
authors.forename: Yuta
authors.initials: Y
authors.lastname: Ishizuka
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Takei
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nawa
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism*; D004347:Drug Interactions; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000172:deficiency / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008636:Mesencephalon / Q000166:cytology / Q000196:embryology / Q000254:growth & development; D051379:Mice; D018345:Mice, Knockout; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D051100:Glial Cell Line-Derived Neurotrophic Factor; D012333:RNA, Messenger; D004815:Epidermal Growth Factor; D014446:Tyrosine 3-Monooxygenase; D066246:ErbB Receptors; D004298:Dopamine