title: Disruption of Smad4 in odontoblasts causes multiple keratocystic odontogenic tumors and tooth malformation in mice.
abstract: Keratocystic odontogenic tumors (KCOTs) are cystic epithelial neoplasias with a high recurrence rate. However, the molecular mechanisms underlying the initiation and progression of KCOTs are still largely unknown. Here, we show that specific ablation of Smad4 in odontoblasts unexpectedly resulted in spontaneous KCOTs in mice. The mutant mice exhibited malformed teeth characterized by fractured incisors and truncated molar roots. These abnormalities were mainly caused by disrupted odontoblast differentiation that led to irregular dentin formation. The cystic tumors arising from the reactivation of epithelial rests of Malassez (ERM), in which Smad4 remained intact, proliferated and formed stratified and differentiated squamous epithelia that exhibited a dramatic upregulation of Hedgehog signaling. Odontoblasts, which are responsive to transforming growth factor beta (TGF-beta)/bone morphogenetic protein (BMP) signals, may produce signal molecules to inhibit the activation of ERM. Indeed, we observed a downregulation of BMP signals from Smad4 mutant odontoblasts to the adjacent Hertwig's epithelial root sheath (HERS). Intriguingly, KCOTs frequently emerged from Smad4-deficient ERM in keratinocyte-specific Smad4 knockout mice, suggesting a novel mechanism in which reciprocal TGF-beta/BMP signaling between odontoblasts and HERS was required for tooth root development and suppression of KCOT formation. These findings provide insight into the genetic basis underlying KCOTs and have important implications for new directions in KCOT treatment.
authors.affiliation: Genetic Laboratory of Development and Diseases, State Key Laboratory of Proteomics, Institute of Biotechnology, Beijing 100071, People's Republic of China.
authors.forename: Yuanrong
authors.initials: Y
authors.lastname: Gao
authors.forename: Guan
authors.initials: G
authors.lastname: Yang
authors.forename: Tujun
authors.initials: T
authors.lastname: Weng
authors.forename: Juan
authors.initials: J
authors.lastname: Du
authors.forename: Xuejiu
authors.initials: X
authors.lastname: Wang
authors.forename: Jian
authors.initials: J
authors.lastname: Zhou
authors.forename: Songlin
authors.initials: S
authors.lastname: Wang
authors.forename: Xiao
authors.initials: X
authors.lastname: Yang
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002454:Cell Differentiation; D003804:Dentin / Q000002:abnormalities / Q000473:pathology / Q000648:ultrastructure; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D018390:Gene Targeting; D019426:Integrases / Q000378:metabolism; D051379:Mice; D009804:Odontoblasts / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D009807:Odontogenic Cysts / Q000150:complications* / Q000473:pathology; D009808:Odontogenic Tumors / Q000150:complications* / Q000473:pathology; D015675:Osteocalcin / Q000378:metabolism; D010641:Phenotype; D015398:Signal Transduction; D051901:Smad4 Protein / Q000378:metabolism*; D014071:Tooth Abnormalities / Q000150:complications* / Q000473:pathology; D014092:Tooth Root / Q000002:abnormalities / Q000473:pathology / Q000648:ultrastructure; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D019485:Bone Morphogenetic Proteins; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D016212:Transforming Growth Factor beta; D015675:Osteocalcin; C045073:Cre recombinase; D019426:Integrases
references.citation: Development. 2000 Apr;127(7):1431-43
references.pmid: 10704389
references.citation: Development. 2008 Jun;135(11):1947-56
references.pmid: 18434416
references.citation: Int J Dev Biol. 1992 Dec;36(4):491-503
references.pmid: 1295560
references.citation: Dev Dyn. 2000 Jul;218(3):480-9
references.pmid: 10878613
references.citation: J Histochem Cytochem. 2000 Feb;48(2):277-84
references.pmid: 10639494
references.citation: Curr Biol. 2002 Jan 8;12(1):47-52
references.pmid: 11790302
references.citation: Mech Dev. 1997 Oct;67(2):111-23
references.pmid: 9392510
references.citation: Gastroenterology. 2009 Jun;136(7):2195-2203.e1-7
references.pmid: 19272384
references.citation: Dev Cell. 2008 Aug;15(2):322-9
references.pmid: 18694570
references.citation: Curr Biol. 2005 Mar 8;15(5):480-8
references.pmid: 15753045
references.citation: Dev Biol. 2007 Mar 1;303(1):191-201
references.pmid: 17196192
references.citation: Development. 2001 Nov;128(22):4523-34
references.pmid: 11714677
references.citation: Cancer Res. 2006 Jul 15;66(14):6972-81
references.pmid: 16849541
references.citation: Dev Cell. 2002 Sep;3(3):439-49
references.pmid: 12361605
references.citation: Int J Dev Biol. 2000 Apr;44(3):337-40
references.pmid: 10853832
references.citation: Dev Dyn. 2006 May;235(5):1167-80
references.pmid: 16450392
references.citation: Cell. 1996 Jun 14;85(6):841-51
references.pmid: 8681379
references.citation: Dev Biol. 2007 Dec 1;312(1):435-47
references.pmid: 17964566
references.citation: J Dent Res. 2003 Mar;82(3):172-6
references.pmid: 12598544
references.citation: Dev Dyn. 2003 Dec;228(4):651-63
references.pmid: 14648842
references.citation: Development. 2000 Apr;127(7):1337-48
references.pmid: 10704381
references.citation: Mech Dev. 2000 Mar 15;92(1):19-29
references.pmid: 10704885
references.citation: Hum Genet. 1997 Oct;100(5-6):497-502
references.pmid: 9341860
references.citation: Evol Dev. 2005 Sep-Oct;7(5):440-57
references.pmid: 16174037
references.citation: Nat Immunol. 2001 Feb;2(2):172-80
references.pmid: 11175816
references.citation: Mol Biol Cell. 2009 Feb;20(3):882-90
references.pmid: 19073883
references.citation: Dev Dyn. 2004 Dec;231(4):758-65
references.pmid: 15499554
references.citation: J Can Dent Assoc. 2008 Mar;74(2):165-165h
references.pmid: 18353202
references.citation: Development. 2009 Apr;136(7):1093-104
references.pmid: 19224984
references.citation: Oral Oncol. 2002 Jun;38(4):323-31
references.pmid: 12076694
references.citation: J Oral Pathol Med. 2003 Feb;32(2):108-13
references.pmid: 12542834
references.citation: Arch Pathol Lab Med. 2004 Mar;128(3):313-7
references.pmid: 14987156
references.citation: Genesis. 2005 May;42(1):33-6
references.pmid: 15830383
references.citation: Cancer Res. 2005 Oct 1;65(19):8671-8
references.pmid: 16204035
references.citation: Mech Dev. 2007 Jul;124(6):409-15
references.pmid: 17449229
references.citation: J Dent Res. 2000 Jun;79(6):1418-22
references.pmid: 10890722
references.citation: Am J Pathol. 2006 Sep;169(3):806-14
references.pmid: 16936257
references.citation: Genes Dev. 1998 Jan 1;12(1):107-19
references.pmid: 9420335
references.citation: Int J Dev Biol. 2003 Feb;47(1):31-9
references.pmid: 12653249
references.citation: J Cell Sci. 2003 May 1;116(Pt 9):1647-8
references.pmid: 12665545
references.citation: Cell. 1995 Sep 22;82(6):969-79
references.pmid: 7553857
references.citation: Genes Dev. 1998 May 15;12(10):1438-52
references.pmid: 9585504
references.citation: Development. 2002 Sep;129(17):4135-46
references.pmid: 12163415
references.citation: Nat Genet. 1999 Jan;21(1):70-1
references.pmid: 9916792
references.citation: Nat Genet. 2000 Apr;24(4):391-5
references.pmid: 10742104
references.citation: Anat Rec A Discov Mol Cell Evol Biol. 2003 Aug;273(2):700-4
references.pmid: 12845706
references.citation: Cell Tissue Res. 2008 Sep;333(3):503-9
references.pmid: 18629540
references.citation: J Biol Chem. 2008 May 2;283(18):12426-37
references.pmid: 18319260
references.citation: Development. 2000 Nov;127(22):4855-66
references.pmid: 11044400
references.citation: Oral Oncol. 2002 Apr;38(3):219-26
references.pmid: 11978543
references.citation: J Med Genet. 2008 May;45(5):303-8
references.pmid: 18285427
references.citation: J Cell Sci. 2007 Jul 1;120(Pt 13):2162-70
references.pmid: 17550966
references.citation: Bone. 2007 Nov;41(5):851-9
references.pmid: 17878071
references.citation: Development. 2007 Oct;134(20):3753-61
references.pmid: 17881493
references.citation: Arch Oral Biol. 2005 Feb;50(2):279-86
references.pmid: 15721162
references.citation: Mol Cell Biol. 2006 Aug;26(16):6197-208
references.pmid: 16880529
references.citation: J Biol Chem. 2008 Jul 11;283(28):19359-70
references.pmid: 18424784
references.citation: Nature. 2006 Jun 22;441(7096):1015-9
references.pmid: 16791201
references.citation: Int J Dev Biol. 1994 Sep;38(3):405-20
references.pmid: 7848824
references.citation: Development. 2001 Jun;128(12):2373-84
references.pmid: 11493556
references.citation: Annu Rev Biochem. 1998;67:753-91
references.pmid: 9759503
references.citation: Oral Oncol. 2002 Jul;38(5):407-15
references.pmid: 12110333
references.citation: Science. 1996 Jun 14;272(5268):1668-71
references.pmid: 8658145
references.citation: Development. 2008 Nov;135(21):3587-97
references.pmid: 18832389