title: c-Myc regulates proliferation and Fgf10 expression in airway smooth muscle after airway epithelial injury in mouse.
abstract: During lung development, Fibroblast growth factor 10 (Fgf10), which is expressed in the distal mesenchyme and regulated by Wnt signaling, acts on the distal epithelial progenitors to maintain them and prevent them from differentiating into proximal (airway) epithelial cells. Fgf10-expressing cells in the distal mesenchyme are progenitors for parabronchial smooth muscle cells (PSMCs). After naphthalene, ozone or bleomycin-induced airway epithelial injury, surviving epithelial cells secrete Wnt7b which then activates the PSMC niche to induce Fgf10 expression. This Fgf10 secreted by the niche then acts on a subset of Clara stem cells to break quiescence, induce proliferation and initiate epithelial repair. Here we show that conditional deletion of the Wnt target gene c-Myc from the lung mesenchyme during development does not affect proper epithelial or mesenchymal differentiation. However, in the adult lung we show that after naphthalene-mediated airway epithelial injury c-Myc is important for the activation of the PSMC niche and as such induces proliferation and Fgf10 expression in PSMCs. Our data indicate that conditional deletion of c-Myc from PSMCs inhibits airway epithelial repair, whereas c-Myc ablation from Clara cells has no effect on airway epithelial regeneration. These findings may have important implications for understanding the misregulation of lung repair in asthma and COPD.
authors: Department of Pediatrics, Division of Cell Biology, National Jewish Health, Denver, Colorado, USA.
authors: Thomas
authors: T
authors: Volckaert
authors: Alice
authors: A
authors: Campbell
authors: Stijn
authors: S
authors: De Langhe
mesh_terms: D000818:Animals; D051526:Fibroblast Growth Factor 10 / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D008168:Lung / Q000254:growth & development / Q000378:metabolism; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism*; D012038:Regeneration / Q000235:genetics; D020545:Respiratory Mucosa / Q000293:injuries* / Q000502:physiology; D055153:Stem Cell Niche / Q000235:genetics; D013234:Stem Cells / Q000378:metabolism
chemical_list: D051526:Fibroblast Growth Factor 10; D016271:Proto-Oncogene Proteins c-myc
references: Dev Dyn. 2004 Dec;231(4):782-94
references: 15499561
references: Lab Invest. 1992 Nov;67(5):553-65
references: 1434534
references: Nature. 2001 Dec 13;414(6865):768-73
references: 11742404
references: Adv Anat Embryol Cell Biol. 2004;176:III-VIII, 1-101, back cover
references: 15079897
references: Curr Opin Immunol. 2008 Apr;20(2):139-48
references: 18472258
references: Dev Cell. 2001 Sep;1(3):435-40
references: 11702954
references: Prog Nucleic Acid Res Mol Biol. 1998;59:135-76
references: 9427842
references: Oncogene. 2013 Oct 17;32(42):5048-57
references: 23246962
references: J Clin Invest. 2009 Jan;119(1):213-24
references: 19104148
references: Cell Stem Cell. 2009 Jun 5;4(6):525-34
references: 19497281
references: Lab Invest. 1976 Sep;35(3):246-57
references: 957607
references: PLoS One. 2008 May 14;3(5):e2142
references: 18478089
references: J Clin Invest. 2009 Sep;119(9):2538-49
references: 19690384
references: Stem Cells. 2012 Sep;30(9):1948-60
references: 22696116
references: Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):12771-5
references: 19625615
references: Am J Pathol. 2002 Jul;161(1):173-82
references: 12107102
references: Physiol Genomics. 2002 Sep 03;10(3):211-5
references: 12209023
references: J Clin Invest. 2010 Jun;120(6):2040-8
references: 20484817
references: J Anat. 1981 Jan;132(Pt 1):71-84
references: 7275793
references: PLoS One. 2008 Jan 30;3(1):e1516
references: 18231602
references: J Clin Invest. 2011 Nov;121(11):4409-19
references: 21985786
references: Cell. 2005 Jun 17;121(6):823-35
references: 15960971
references: Genes Dev. 2004 Jan 15;18(2):126-31
references: 14729569
references: J Cell Biol. 2009 Jan 26;184(2):309-22
references: 19171760
references: Nature. 2007 Apr 5;446(7136):676-9
references: 17377531
references: Dis Model Mech. 2010 Sep-Oct;3(9-10):545-56
references: 20699479
references: Am J Respir Cell Mol Biol. 2006 Feb;34(2):151-7
references: 16239640
references: Annu Rev Cell Dev Biol. 2011;27:493-512
references: 21639799
references: Nature. 2004 Apr 1;428(6982):564-9
references: 15024390
references: Development. 2006 Jul;133(13):2455-65
references: 16735479
references: Dev Biol. 2003 Jun 1;258(1):185-200
references: 12781692
references: Development. 2005 Mar;132(6):1363-74
references: 15716345
references: Dev Cell. 2011 Aug 16;21(2):257-72
references: 21839920
references: Development. 2006 May;133(9):1611-24
references: 16613830
references: Dev Cell. 2009 Aug;17(2):290-8
references: 19686689
references: Oncogene. 2006 Mar 30;25(14):2105-12
references: 16288213
references: Dev Biol. 2011 Aug 15;356(2):541-52
references: 21704027
references: BMC Dev Biol. 2008 Jan 10;8:2
references: 18186922
references: Cell Cycle. 2006 Feb;5(3):223-6
references: 16397414
references: Development. 2003 Jul;130(13):3063-74
references: 12756187
references: Cell. 2012 Mar 30;149(1):22-35
references: 22464321
references: Dev Biol. 2007 Jul 15;307(2):237-47
references: 17560563
references: J Biol Chem. 2012 Feb 10;287(7):5164-72
references: 22203675
references: Curr Top Microbiol Immunol. 2004;280:1-70
references: 14594207
references: Pediatr Res. 2009 Oct;66(4):386-90
references: 19581825
references: Development. 2009 Nov;136(22):3741-5
references: 19855016
references: Am J Physiol Lung Cell Mol Physiol. 2003 Oct;285(4):L838-46
references: 12818887
references: Dev Biol. 2008 Jul 15;319(2):426-36
references: 18533146
references: Am J Respir Cell Mol Biol. 2010 Jan;42(1):21-31
references: 19329555
references: Dev Biol. 2006 Nov 1;299(1):52-62
references: 16989802
references: Proc Am Thorac Soc. 2006 Aug;3(6):510-1
references: 16921131
references: Development. 2005 May;132(9):2157-66
references: 15800000
references: J Clin Invest. 2009 Apr;119(4):772-87
references: 19287097
references: Nature. 2008 Oct 2;455(7213):627-32
references: 18754011
references: Development. 1997 Dec;124(23):4867-78
references: 9428423
references: Am J Pathol. 2000 Jan;156(1):269-78
references: 10623675
references: Development. 2011 Jan;138(2):273-82
references: 21148187
references: Am J Respir Cell Mol Biol. 2001 Jun;24(6):671-81
references: 11415931
references: Nat Cell Biol. 2009 Feb;11(2):190-6
references: 19098901
references: Am J Physiol Cell Physiol. 2004 Jul;287(1):C171-81
references: 15189821
references: Am J Physiol. 1995 Dec;269(6 Pt 1):L791-9
references: 8572241