Lef1 may contribute to agenesis of the third molars in mice

Takehiko Shimizu, Takahiro Ichinosawa, Yuri Kiguchi, Fusae Ishida, Takahide Maeda

Department of Pediatric Dentistry, Nihon University School of Dentistry at Matsudo, Chiba, Japan.

DOI: 10.4236/ojst.2013.35047                

Abstract

Tooth agenesis is the most common developmental anomaly of the human dentition. Epilepsy-like disorder (EL) mice, which have a 100% incidence of agenesis of the third molars, may be a good model for the genetic study of human tooth agenesis. Our previous congenic breeding strategy using EL mice confined a major locus for agenesis of M3, designated am3, within an approximately 1 Mega base pair (Mbp) interval on chromosome 3, which contains five known genes; Lef1, Hadh, Cyp2u1, Sgms2 and Papss1. The aim of this study was to identify the strongest candidate for am3 among the five genes using real-time PCR analysis. The tooth germs of M3 in the bud stage of EL and control mice were dissected out, and total RNA was extracted. In real-time PCR analysis, a significantly low level of expression of Lef1, which is one of the essential transcription factors for early tooth development, was observed in M3 of EL mice. In addition, a significantly low level of expression of Fgf4, which is a direct transcriptional target for LEF1 in early tooth development, was observed in M3 of EL mice. Our results suggest that the cause of M3 agenesis of EL mice may be a low level of Lef1 expression in M3 in the bud stage of EL mice.

Keywords

Hypodontia; Gene Expression; EL Mice

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Boeira Jr., B.R. and Echeverrigaray, S. (2012) Polymorphism in the MSX1 gene in a family with upper lateral incisor agenesis. Archives of Oral Biology, 57, 1423-1428. doi:10.1016/j.archoralbio.2012.04.008
[2]	Mostowska, A., Biedziak, B. and Jagodzinski, P.P. (2012) Novel MSX1 mutation in a family with autosomal-dominant hypodontia of second premolars and third molars. Archives of Oral Biology, 57, 790-795. doi:10.1016/j.archoralbio.2012.01.003
[3]	Belloni, E., Muenke, M., Roessler, E., Traverso, G., Siegel-Bartelt, J., Frumkin, A., Mitchell, H.F., Donis-Keller, H., Helms, C., Hing, A.V., Heng, H.H., Koop, B., Martindale, D., Rommens, J.M., Tsui, L.C. and Scherer, S.W. (1996) Identification of Sonic hedgehog as a candidate gene responsible for holoprosencephaly. Nature Genetics, 14, 353-356. doi:10.1038/ng1196-353
[4]	Semina, E.V., Reiter, R., Leysens, N.J., Alward, W.L., Small, K.W., Datson, N.A., Siegel-Bartelt, J., Bierke-Nelson, D., Bitoun, P., Zabel, B.U., Carey, J.C. and Murray, J.C. (1996) Cloning and characterization of a novel bicoidrelated homeobox transcription factor gene, RIEG, involved in Rieger syndrome. Nature Genetics, 14, 392-399. doi:10.1038/ng1296-392
[5]	Kondo, S., Schutte, B.C., Richardson, R.J., Bjork, B.C., Knight, A.S., Watanabe, Y., Howard, E., de Lima, R.L., Daack-Hirsch, S., Sander, A., McDonald-McGinn, D.M., Zackai, E.H., Lammer, E.J., Aylsworth, A.S., Ardinger, H.H., Lidral, A.C., Pober, B.R., Moreno, L., Arcos-Burgos, M., Valencia, C., Houdayer, C., Bahuau, M., Moretti-Ferreira, D., Richieri-Costa, A., Dixon, M.J. and Murray, J.C. (2002) Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes. Nature Genetics, 32, 285-289. doi:10.1038/ng985
[6]	Celli, J., Duijf, P., Hamel, B.C., Bamshad, M., Kramer, B., Smits, A.P., Newbury-Ecob, R., Hennekam, R.C., Van Buggenhout, G., van Haeringen, A., Woods, C.G., van Essen, A.J., de Waal, R., Vriend, G., Haber, D.A., Yang, A., McKeon, F., Brunner, H.G. and van Bokhoven, H. (1999) Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome. Cell, 99, 143-153. doi:10.1016/S0092-8674(00)81646-3
[7]	Vastardis, H., Karimbux, N., Guthua, S.W., Seidman, J.G. and Seidman, C.E. (1996) A human MSX1 homeodomain missense mutation causes selective tooth agenesis. Nature Genetics, 13, 417-421. doi:10.1038/ng0896-417
[8]	Stockton, D.W., Das, P., Goldenberg, M., D’Souza, R.N. and Patel, P.I. (2000) Mutation of PAX9 is associated with oligodontia. Nature Genetics, 24, 18-19. doi:10.1038/71634
[9]	Lammi, L., Arte, S., Somer, M., Jarvinen, H., Lahermo, P., Thesleff, I., Pirinen, S. and Nieminen, P. (2004) Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer. American Journal of Human Genetics, 74, 1043-1050. doi:10.1086/386293
[10]	Kantaputra, P. and Sripathomsawat, W. (2011) WNT10A and isolated hypodontia. American Journal of Medical Genetics Part A, 155A, 1119-1122. doi:10.1002/ajmg.a.33840
[11]	Tao, R., Jin, B., Guo, S.Z., Qing, W., Feng, G.Y., Brooks, D.G., Liu, L., Xu, J., Li, T., Yan, Y. and He, L. (2006) A novel missense mutation of the EDA gene in a Mongolian family with congenital hypodontia. Journal of Human Genetics, 51, 498-502. doi:10.1007/s10038-006-0389-2
[12]	Azeem, Z., Naqvi, S.K., Ansar, M., Wali, A., Naveed, A.K., Ali, G., Hassan, M.J., Tariq, M., Basit, S. and Ahmad, W. (2009) Recurrent mutations in functionally-related EDA and EDAR genes underlie X-linked isolated hypodontia and autosomal recessive hypohidrotic ectodermal dysplasia. Archives of Dermatological Research, 301, 625-629. doi:10.1007/s00403-009-0975-1
[13]	Bergendal, B., Klar, J., Stecksén-Blicks, C., Norderyd, J. and Dahl, N. (2011) Isolated oligodontia associated with mutations in EDARADD, AXIN2, MSX1, and PAX9 genes. American Journal of Medical Genetics Part A, 155A, 1616-1622. doi:10.1002/ajmg.a.34045
[14]	Nieminen, P., Arte, S., Pirinen, S., Peltonen, L. and Thesleff, I. (1995) Gene defect in hypodontia: Exclusion of MSX1 and MSX2 as candidate genes. Human Genetics, 96, 305-308. doi:10.1007/BF00210412
[15]	Arte, S., Nieminen, P., Pirinen, S., Thesleff, I. and Peltonen, L. (1996) Gene defect in hypodontia: Exclusion of EGF, EGFR, and FGF3 as candidate genes. Journal of Dental Research, 75, 1346-1352. doi:10.1177/00220345960750060401
[16]	Goldenberg, M., Das, P., Messersmith, M., Stockton, D.W., Patel, P.I. and D’Souza, R.N. (2000) Clinical, radiographic, and genetic evaluation of a novel form of autosomal-dominant oligodontia. Journal of Dental Research, 79, 1469-1475. doi:10.1177/00220345000790070701
[17]	Scarel, R.M., Trevilatto, P.C., Di Hipolito Jr., O., Camargo, L.E. and Line, S.R. (2000) Absence of mutations in the homeodomain of the MSX1 gene in patients with hypodontia. American Journal of Medical Genetics, 92, 346-349. doi:10.1002/1096-8628(20000619)92:5<346::AID-AJMG10>3.0.CO;2-A
[18]	Gerits, A., Nieminen, P., De Muynck, S. and Carels, C. (2006) Exclusion of coding region mutations in MSX1, PAX9 and AXIN2 in eight patients with severe oligodontia phenotype. Orthodontics & Craniofacial Research, 9, 129-136. doi:10.1111/j.1601-6343.2006.00367.x
[19]	Imaizumi, K. and Nakano, T. (1964) Mutant stocks, strain El. Mouse News Letter, 31, 57.
[20]	Asada, Y., Shimizu, T., Matsune, K., Shimizu, K., Suzuki, Y., Takamori, K. and Maeda, T. (2000) Absence of the third molars in strain EL mice. Pediatric Dental Journal, 10, 19-22.
[21]	Nomura, R., Shimizu, T., Asada, Y., Hirukawa, S. and Maeda, T. (2003) Genetic mapping of absence of the third molars in EL mice to chromosome 3. Journal of Dental Research, 82, 786-790. doi:10.1177/154405910308201005
[22]	Shimizu, T., Han, J., Asada, Y., Okamoto, H. and Maeda, T. (2005) Localization of am3 using EL Congenic Mouse Strains. Journal of Dental Research, 84, 315-319. doi:10.1177/154405910508400404
[23]	Shimizu, T., Morita, W. and Maeda, T. (2013) Genetic mapping of agenesis of the third molars in mice. Bio-chemical Genetics. doi:10.1007/s10528-013-9602-0
[24]	Kratochwil, K., Galceran, J., Tontsch, S., Roth, W. and Grosschedl, R. (2002) FGF4, a direct target of LEF1 and Wnt signaling, can rescue the arrest of tooth organogenesis in Lef1(-/-) mice. Genes & Development, 16, 3173-3185. doi:10.1101/gad.1035602
[25]	van Genderen, C., Okamura, R.M., Farinas, I., Quo, R.G., Parslow, T.G., Bruhn, L. and Grosschedl, R. (1994) Development of several organs that require inductive epithelial-mesenchymal interactions is impaired in LEF-1-deficient mice. Genes & Development, 8, 2691-2703. doi:10.1101/gad.8.22.2691
[26]	Chen, J., Lan, Y., Baek, J.A., Gao, Y. and Jiang, R. (2009) Wnt/betacatenin signaling plays an essential role in activation of odontogenic mesenchyme during early tooth development. Developmental Biology, 334, 174-185. doi:10.1016/j.ydbio.2009.07.015
[27]	Sasaki, T., Ito, Y., Xu, X., Han, J., Bringas, P. Jr., Maeda, T. Slavkin, H.C., Grosschedl, R. and Chai, Y. (2005) LEF1 is a critical epithelial survival factor during tooth morphogenesis. Developmental Biology, 278, 130-143. doi:10.1016/j.ydbio.2004.10.021
[28]	Clayton, P.T., Eaton, S., Aynsley-Green, A., Edginton, M., Hussain, K., Krywawych, S., Datta, V., Malingre, H.E., Berger, R. and van den Berg, I.E. (2001) Hyperinsulinism in short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency reveals the importance of betaoxidation in insulin secretion. Journal of Clinical Investigation, 108, 457-465.
[29]	Liu, J., Zhang, H., Li, Z., Hailemariam, T.K., Chakraborty, M., Jiang, K., Qiu, D., Bui, H.H., Peake, D.A., Kuo, M.S., Wadgaonkar, R., Cao, G. and Jiang, X.C. (2009) Sphingomyelin synthase 2 is one of the determinants for plasma and liver sphingomyelin levels in mice. Arteriosclerosis, Thrombosis, and Vascular Biology, 29, 850-856. doi:10.1161/ATVBAHA.109.185223
[30]	Sekulic, N., Dietrich, K., Paarmann, I., Ort, S., Konrad, M. and Lavie, A. (2007) Elucidation of the active conformation of the APS-kinase domain of human PAPS synthetase 1. Journal of Molecular Biology, 367, 488-500. doi:10.1016/j.jmb.2007.01.025
[31]	Choudhary, D., Jansson, I., Stoilov, I., Sarfarazi, M. and Schenkman, J.B. (2005) Expression patterns of mouse and human CYP orthologs (families 1-4) during development and in different adult tissues. Archives of Bio-chemistry and Biophysics, 436, 50-61. doi:10.1016/j.abb.2005.02.001