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.
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Univ E Anglia, Sch Biol Sci, Norwich NR4 7TJ, Norfolk, EnglandUniv E Anglia, Mol Biol Res Grp, Norwich NR4 7TJ, Norfolk, England
Sweetman, Dylan
Goljanek, Katarzyna
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Univ E Anglia, Sch Biol Sci, Norwich NR4 7TJ, Norfolk, EnglandUniv E Anglia, Mol Biol Res Grp, Norwich NR4 7TJ, Norfolk, England
Goljanek, Katarzyna
Rathjen, Tina
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Univ E Anglia, Mol Biol Res Grp, Norwich NR4 7TJ, Norfolk, England
Univ E Anglia, Sch Biol Sci, Norwich NR4 7TJ, Norfolk, EnglandUniv E Anglia, Mol Biol Res Grp, Norwich NR4 7TJ, Norfolk, England
Rathjen, Tina
Oustanina, Svetlana
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Max Planck Inst Heart & Lung Res, D Bad Nauheim, GermanyUniv E Anglia, Mol Biol Res Grp, Norwich NR4 7TJ, Norfolk, England
Oustanina, Svetlana
Braun, Thomas
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Max Planck Inst Heart & Lung Res, D Bad Nauheim, GermanyUniv E Anglia, Mol Biol Res Grp, Norwich NR4 7TJ, Norfolk, England
Braun, Thomas
Dalmay, Tamas
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Univ E Anglia, Mol Biol Res Grp, Norwich NR4 7TJ, Norfolk, England
Univ E Anglia, Sch Biol Sci, Norwich NR4 7TJ, Norfolk, EnglandUniv E Anglia, Mol Biol Res Grp, Norwich NR4 7TJ, Norfolk, England
Dalmay, Tamas
Munsterberg, Andrea
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Univ E Anglia, Sch Biol Sci, Norwich NR4 7TJ, Norfolk, EnglandUniv E Anglia, Mol Biol Res Grp, Norwich NR4 7TJ, Norfolk, England
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Kyoto Prefectural Univ Med, Grad Sch Med Sci, Dept Pediat, Kamigyo Ku, Kyoto 6028566, JapanKyoto Prefectural Univ Med, Grad Sch Med Sci, Dept Pediat, Kamigyo Ku, Kyoto 6028566, Japan
Tsuchiya, Kunihiko
Yoshida, Hideki
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Kyoto Prefectural Univ Med, Grad Sch Med Sci, Dept Pediat, Kamigyo Ku, Kyoto 6028566, JapanKyoto Prefectural Univ Med, Grad Sch Med Sci, Dept Pediat, Kamigyo Ku, Kyoto 6028566, Japan
Yoshida, Hideki
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Yagyu, Shigeki
Kikuchi, Ken
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Kyoto Prefectural Univ Med, Grad Sch Med Sci, Dept Pediat, Kamigyo Ku, Kyoto 6028566, JapanKyoto Prefectural Univ Med, Grad Sch Med Sci, Dept Pediat, Kamigyo Ku, Kyoto 6028566, Japan
Kikuchi, Ken
Misawa, Akiko
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Kyoto Prefectural Univ Med, Grad Sch Med Sci, Dept Pediat, Kamigyo Ku, Kyoto 6028566, JapanKyoto Prefectural Univ Med, Grad Sch Med Sci, Dept Pediat, Kamigyo Ku, Kyoto 6028566, Japan
Misawa, Akiko
Iehara, Tomoko
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Kyoto Prefectural Univ Med, Grad Sch Med Sci, Dept Pediat, Kamigyo Ku, Kyoto 6028566, JapanKyoto Prefectural Univ Med, Grad Sch Med Sci, Dept Pediat, Kamigyo Ku, Kyoto 6028566, Japan
Iehara, Tomoko
Hosoi, Hajime
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Kyoto Prefectural Univ Med, Grad Sch Med Sci, Dept Pediat, Kamigyo Ku, Kyoto 6028566, JapanKyoto Prefectural Univ Med, Grad Sch Med Sci, Dept Pediat, Kamigyo Ku, Kyoto 6028566, Japan
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W Virginia Univ, Robert C Byrd Hlth Sci Ctr, Dept Anat, Morgantown, WV 26506 USAW Virginia Univ, Robert C Byrd Hlth Sci Ctr, Dept Anat, Morgantown, WV 26506 USA
Dey, RD
Satterfield, B
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W Virginia Univ, Robert C Byrd Hlth Sci Ctr, Dept Anat, Morgantown, WV 26506 USAW Virginia Univ, Robert C Byrd Hlth Sci Ctr, Dept Anat, Morgantown, WV 26506 USA
Satterfield, B
Altemus, JB
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W Virginia Univ, Robert C Byrd Hlth Sci Ctr, Dept Anat, Morgantown, WV 26506 USAW Virginia Univ, Robert C Byrd Hlth Sci Ctr, Dept Anat, Morgantown, WV 26506 USA