title: Trigenic neural crest-restricted Smad7 over-expression results in congenital craniofacial and cardiovascular defects.
abstract: Smad7 is a negative regulator of TGFbeta superfamily signaling. Using a three-component triple transgenic system, expression of the inhibitory Smad7 was induced via doxycycline within the NCC lineages at pre- and post-migratory stages. Consistent with its role in negatively regulating both TGFbeta and BMP signaling in vitro, induction of Smad7 within the NCC significantly suppressed phosphorylation levels of both Smad1/5/8 and Smad2/3 in vivo, resulting in subsequent loss of NCC-derived craniofacial, pharyngeal and cardiac OFT cushion cells. At the cellular level, increased cell death was observed in pharyngeal arches. However, cell proliferation and NCC-derived smooth muscle differentiation were unaltered. NCC lineage mapping demonstrated that cardiac NCC emigration and initial migration were not affected, but subsequent colonization of the OFT was significantly reduced. Induction of Smad7 in post-migratory NCC resulted in interventricular septal chamber septation defects, suggesting that TGFbeta superfamily signaling is also essential for cardiac NCC at post-migratory stages to govern normal cardiac development. Taken together, the data illustrate that tightly regulated TGFbeta superfamily signaling plays an essential role during craniofacial and cardiac NCC colonization and cell survival in vivo.
authors.affiliation: Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Sunyong
authors.initials: S
authors.lastname: Tang
authors.forename: Paige
authors.initials: P
authors.lastname: Snider
authors.forename: Antony B
authors.initials: AB
authors.lastname: Firulli
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Conway
mesh_terms: D000818:Animals; D001934:Branchial Region / Q000002:abnormalities; D002318:Cardiovascular Diseases / Q000151:congenital / Q000235:genetics; D019070:Cell Lineage; D002470:Cell Survival; D019465:Craniofacial Abnormalities / Q000235:genetics; D005786:Gene Expression Regulation; D051379:Mice; D008954:Models, Biological; D008957:Models, Genetic; D009206:Myocardium / Q000378:metabolism; D009432:Neural Crest / Q000378:metabolism*; D051906:Smad7 Protein / Q000235:genetics* / Q000502:physiology*; D015533:Transcriptional Activation; D019076:Transgenes
chemical_list: D051906:Smad7 Protein; C497807:Smad7 protein, mouse
references.citation: Curr Opin Cell Biol. 2007 Apr;19(2):176-84
references.pmid: 17317136
references.citation: Mech Dev. 2002 Jan;110(1-2):139-49
references.pmid: 11744375
references.citation: Int J Cancer. 2003 Apr 20;104(4):446-9
references.pmid: 12584741
references.citation: J Anat. 2005 Nov;207(5):575-601
references.pmid: 16313393
references.citation: Development. 2001 Apr;128(8):1253-64
references.pmid: 11262227
references.citation: BMC Dev Biol. 2006 Nov 01;6:51
references.pmid: 17078885
references.citation: Development. 2006 Jan;133(2):371-81
references.pmid: 16368934
references.citation: Mech Dev. 2001 Dec;109(2):253-65
references.pmid: 11731238
references.citation: Lancet. 2007 Oct 20;370(9596):1443-52
references.pmid: 17950858
references.citation: Development. 1997 Jan;124(2):505-14
references.pmid: 9053326
references.citation: Nucleic Acids Res. 2005 Mar 22;33(5):e51
references.pmid: 15784609
references.citation: Dev Cell. 2006 Sep;11(3):301-12
references.pmid: 16950122
references.citation: Cell. 1997 Jun 27;89(7):1165-73
references.pmid: 9215638
references.citation: Blood. 2005 Mar 1;105(5):1905-15
references.pmid: 15498852
references.citation: Dev Dyn. 1997 Jan;208(1):34-47
references.pmid: 8989519
references.citation: Genes Dev. 2005 Dec 1;19(23):2783-810
references.pmid: 16322555
references.citation: Cancer Res. 2004 May 15;64(10):3599-606
references.pmid: 15150118
references.citation: Transgenic Res. 2002 Feb;11(1):21-9
references.pmid: 11874100
references.citation: Bioessays. 2000 Aug;22(8):708-16
references.pmid: 10918301
references.citation: Genesis. 2009 Jul;47(7):469-75
references.pmid: 19415626
references.citation: Cardiovasc Res. 2000 Aug;47(2):314-28
references.pmid: 10946068
references.citation: Dev Biol. 2007 Dec 1;312(1):435-47
references.pmid: 17964566
references.citation: Dev Biol. 2006 Nov 15;299(2):517-28
references.pmid: 17014840
references.citation: Curr Opin Genet Dev. 2002 Aug;12(4):452-8
references.pmid: 12100892
references.citation: Genes Dev. 1998 Jan 15;12(2):186-97
references.pmid: 9436979
references.citation: Genome Res. 2007 Apr;17(4):482-91
references.pmid: 17351135
references.citation: Nature. 1997 Oct 9;389(6651):631-5
references.pmid: 9335507
references.citation: Pediatr Res. 2005 Feb;57(2):169-76
references.pmid: 15611355
references.citation: ScientificWorldJournal. 2007 Jul 03;7:1090-113
references.pmid: 17619792
references.citation: J Clin Invest. 2009 Nov;119(11):3301-10
references.pmid: 19855134
references.citation: Development. 2009 Nov;136(22):3699-714
references.pmid: 19855013
references.citation: Proc Natl Acad Sci U S A. 2006 Feb 7;103(6):1858-63
references.pmid: 16443684
references.citation: Development. 2002 Oct;129(19):4591-603
references.pmid: 12223415
references.citation: Dev Biol. 2009 Jun 15;330(2):329-38
references.pmid: 19361496
references.citation: Genes Dev. 2005 Mar 1;19(5):530-5
references.pmid: 15741317
references.citation: Biochim Biophys Acta. 2007 Feb;1769(2):149-52
references.pmid: 17306381
references.citation: Dev Biol. 2008 Mar 15;315(2):369-82
references.pmid: 18243171
references.citation: Dev Dyn. 2006 Sep;235(9):2507-20
references.pmid: 16894609
references.citation: Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3789-94
references.pmid: 9108056
references.citation: J Embryol Exp Morphol. 1981 Aug;64:105-20
references.pmid: 7031165
references.citation: Development. 2000 Mar;127(5):1095-104
references.pmid: 10662648
references.citation: Mech Dev. 1995 Aug;52(2-3):275-89
references.pmid: 8541216
references.citation: Development. 1992 Oct;116(2):297-307
references.pmid: 1283734
references.citation: Development. 2005 Mar;132(5):851-61
references.pmid: 15705856
references.citation: Dev Biol. 2008 Apr 15;316(2):417-30
references.pmid: 18334251
references.citation: Development. 2000 May;127(9):1869-78
references.pmid: 10751175
references.citation: Semin Cell Dev Biol. 2007 Feb;18(1):101-10
references.pmid: 17224285
references.citation: J Biol Chem. 2009 Jan 2;284(1):292-300
references.pmid: 18952608
references.citation: Nature. 2008 Dec 18;456(7224):957-61
references.pmid: 19078960
references.citation: J Clin Invest. 2004 Jan;113(2):253-64
references.pmid: 14722617
references.citation: Nat Med. 2003 Feb;9(2):173-82
references.pmid: 12539040
references.citation: Cell. 2008 Jul 25;134(2):215-30
references.pmid: 18662538
references.citation: Dev Biol. 1994 Aug;164(2):409-19
references.pmid: 8045344
references.citation: Cell. 1996 May 3;85(3):331-43
references.pmid: 8616889
references.citation: Proc Natl Acad Sci U S A. 2009 Sep 8;106(36):15436-41
references.pmid: 19706403
references.citation: Nat Rev Genet. 2002 Jun;3(6):453-61
references.pmid: 12042772
references.citation: Circ Res. 2007 Feb 2;100(2):220-8
references.pmid: 17218603
references.citation: Development. 2003 Nov;130(21):5269-80
references.pmid: 12975342
references.citation: Science. 2002 Aug 2;297(5582):848-51
references.pmid: 12161657
references.citation: Development. 2002 Jan;129(2):527-38
references.pmid: 11807043
references.citation: Genesis. 2003 Jan;35(1):1-21
references.pmid: 12481294
references.citation: Development. 2000 Apr;127(8):1671-9
references.pmid: 10725243
references.citation: Nat Genet. 1999 Jan;21(1):70-1
references.pmid: 9916792
references.citation: Development. 2004 May;131(9):2205-18
references.pmid: 15073157
references.citation: Development. 2009 Nov;136(21):3575-84
references.pmid: 19793887
references.citation: Circ Res. 1995 Aug;77(2):211-5
references.pmid: 7614707
references.citation: Dev Dyn. 2000 Aug;218(4):663-70
references.pmid: 10906784
references.citation: Cell Tissue Res. 2000 Jul;301(1):43-52
references.pmid: 10928280
references.citation: PLoS One. 2009 Jun 25;4(6):e6049
references.pmid: 19557177
references.citation: Dev Cell. 2006 Jan;10(1):71-80
references.pmid: 16399079
references.citation: Development. 2000 Apr;127(8):1607-16
references.pmid: 10725237
references.citation: Mech Dev. 2001 Mar;101(1-2):209-12
references.pmid: 11231077
references.citation: Dev Biol. 2006 Jan 15;289(2):420-9
references.pmid: 16332365
references.citation: Mech Dev. 2007 Sep-Oct;124(9-10):729-45
references.pmid: 17693062
references.citation: J Pediatr. 2009 Oct;155(4):560-5
references.pmid: 19595366
references.citation: Dev Biol. 2007 Nov 1;311(1):172-84
references.pmid: 17916348
references.citation: Nature. 2002 Aug 8;418(6898):641-6
references.pmid: 12167862
references.citation: Dev Biol. 1998 Jun 1;198(1):1-12
references.pmid: 9640328
references.citation: Mol Cell Biol. 2005 Dec;25(24):11131-44
references.pmid: 16314533
references.citation: Science. 2004 Feb 13;303(5660):1020-3
references.pmid: 14716020
references.citation: Development. 2004 Jul;131(14):3481-90
references.pmid: 15226263
references.citation: Hum Mol Genet. 2009 Jan 1;18(1):142-50
references.pmid: 18838463
references.citation: PLoS Biol. 2006 Feb;4(2):e39
references.pmid: 16435884
references.citation: Mech Dev. 2004 Feb;121(2):173-82
references.pmid: 15037318
references.citation: Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):17115-20
references.pmid: 18952847
references.citation: J Biol Chem. 1999 May 7;274(19):13637-42
references.pmid: 10224135
references.citation: Arch Ophthalmol. 2007 May;125(5):647-54
references.pmid: 17502504
references.citation: Nature. 2007 Nov 8;450(7167):180-1
references.pmid: 17994078
references.citation: Development. 2006 Sep;133(18):3629-39
references.pmid: 16914489
references.citation: J Clin Invest. 2001 Aug;108(4):601-9
references.pmid: 11518734
references.citation: Genesis. 2008 Mar;46(3):167-76
references.pmid: 18327771