A Shh/miR-206/BDNF cascade coordinates innervation and formation of airway smooth muscle.
Dysfunctional neural control of airway smooth muscle (ASM) is involved in inflammatory diseases, such as asthma. However, neurogenesis in the lung is poorly understood. This study uses mouse models to investigate developmental mechanisms of ASM innervation, a process that is highly coordinated with ASM formation during lung branching morphogenesis. We show that brain-derived neurotrophic factor (BDNF) is an essential ASM-derived signal for innervation. Although BDNF mRNA expression is temporally dissociated with ASM formation and innervation, BDNF protein is coordinately produced through post-transcriptional suppression by miR-206. Using a combination of chemical and genetic approaches to modulate sonic hedgehog (Shh) signaling, a pathway essential for lung branching and ASM formation, we show that Shh signaling blocks miR-206 expression, which in turn increases BDNF protein expression. Together, our work uncovers a functional cascade that involves Shh, miR-206 and BDNF to coordinate ASM formation and innervation.
The Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Kelsi
K
Radzikinas
Linh
L
Aven
Zhihua
Z
Jiang
Thanh
T
Tran
Jesus
J
Paez-Cortez
Karthik
K
Boppidi
Jining
J
Lu
Alan
A
Fine
Xingbin
X
Ai
D000367:Age Factors; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009130:Muscle, Smooth / Q000294:innervation / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D012137:Respiratory System / Q000033:anatomy & histology* / Q000196:embryology / Q000294:innervation*; D015398:Signal Transduction / Q000235:genetics; D014404:Tubulin / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D053823:Hedgehog Proteins; D035683:MicroRNAs; C540669:Mirn206 microRNA, mouse; D012333:RNA, Messenger; C465570:Shh protein, mouse; D014404:Tubulin; C462941:beta3 tubulin, mouse; D049452:Green Fluorescent Proteins