Abstract
The hairy ears (Eh) mutation in the mouse originated from neutron irradiation experiments and is associated with chromosomal inversion on chromosome 15. Eh/+ mice have small pinna and extra hairs on the pinna but the phenotypic features of Eh/Eh mice are unclear. In this study we found that Eh/Eh mice died shortly after birth and had a cleft palate caused by impaired growth of palate shelves. Because genes located on the breakpoints of inversion are likely to be responsible for the defects associated with chromosomal inversions, we determined the breakpoints of the Eh inversion. We used a new genetic method that uses recombinant chromosomes resulting from crossing over between two overlapping inversions to determine the breakpoints. Koa is a mouse mutation associated with inversion of chromosome 15, which partially overlaps with the Eh inversion. We made Eh +/+ Koa double heterozygotes and obtained the recombinant chromosomes possessing deletion and duplication of the regions flanked by the breakpoints of both inversions, which were generated by crossing over within the overlapped region of these inversions. By defining the deleted regions we identified the breakpoints of the Eh inversion. We then examined the expression of genes in the vicinities of the breakpoints and found ectopic expression of the Hoxc5 gene and a transcript with unknown function in the developing palate of Eh/Eh mice, which is likely to be responsible for the cleft palate.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Asada H, Kawamura Y, Maruyama K, Kume H, Ding RG, et al. (1997) Cleft palate and decreased brain γ-aminobutyric acid in mice lacking the 67-kDa isoform of glutamic acid decarboxylase. Proc Natl Acad Sci USA 94:6496–6499
Balling R, Mutter G, Gruss P, Kessel M (1989) Craniofacial abnormalities induced by ectopic expression of the homeobox gene Hox-1.1 in transgenic mice. Cell 58:337–347
Bangham JW (1965) Hairy ears, Eh. Mouse News Lett 33:68
Beechey CV (1994) List of chromosome anomalies. Mouse Genome 92:336–347
Condie BG, Bain G, Gottlieb DI, Capecchi MR (1997) Cleft palate in mice with a targeted mutation in the γ-aminobutyric acid-producing enzyme glutamic acid decarboxylase 67. Proc Natl Acad Sci USA 94:11451–11455
Davisson MT, Roderick TH, Akeson EC, Hawes NL, Sweet HO (1990) The hairy ears (Eh) mutation is closely associated with a chromosomal rearrangement in mouse chromosome 15. Genet Res 56:167–178
Ferguson MWJ (1988) Palate development. Development 103:41–60
Gritli-Linde A (2007) Molecular control of secondary palate development. Dev Biol 301:309–326
Hagiwara N, Klewer SE, Samson RA, Erickson DT, Lyon MF, et al. (2000) Sox6 is a candidate gene for p 100H myopathy, heart block, and sudden neonatal death. Proc Natl Acad Sci USA 97:4180–4185
Homanics GE, DeLorey TM, Firestone LL, Quinlan JJ, Handforth A, et al. (1997) Mice devoid of γ-aminobutyrate type A receptor β3 subunit have epilepsy, cleft palate, and hypersensitive behavior. Proc Natl Acad Sci USA 94:4143–4148
Hough RB, Lengeling A, Bedian V, Lo C, Bucan M (1998) Rump white inversion in the mouse disrupts dipeptidyl aminopeptidase-like protein 6 and cause dysregulation of Kit expression. Proc Natl Acad Sci USA 95:13800–13805
Jugessur A, Murray JC (2005) Orofacial clefting: recent insights into a complex trait. Curr Opin Genet Dev 15:270–278
Kaur S, Singh G, Stock JL, Schreiner CM, Kier AB, et al. (1992) Dominant mutation of the murine Hox-2.2 gene results in developmental abnormalities. J Exp Zool 264:323–336
Kmita M, Fraudeau N, Herault Y, Duboule D (2002) Serial deletions and duplications suggest a mechanism for the collinearity of Hoxd genes in limbs. Nature 420:145–150
Lan Y, Ovitt CE, Cho E-S, Maltby KM, Wang Q, et al. (2004) Odd-skipped related 2 (Osr2) encodes a key intrinsic regulator of secondary palate growth and morphogenesis. Development 131:3207–3216
Mattick JS, Makunin IV (2005) Small regulatory RNAs in mammals. Hum Mol Genet 14 Spec No 1:R121–R132
McLain K, Schreiner C, Yager KL, Stock JL, Potter SS (1992) Ectopic expression of Hox-2.3 induces craniofacial and skeletal malformations in transgenic mice. Mech Dev 39:3–16
Miettinen PJ, Chin JR, Shum L, Slavkin HC, Shuler CF, et al. (1999) Epidermal growth factor receptor function is necessary for normal craniofacial development and palate closure. Nat Genet 22:69–73
Murray JC (2002) Gene/environment causes of cleft lip and/or palate. Clin Genet 61:248–256
Niedermaier M, Schwabe GC, Fees S, Helmrich A, Brieske N, et al. (2005) An inversion involving the mouse Shh locus results in brachydactyly through dysregulation of Shh expression. J Clin Invest 115:900–909
Noguchi J, Kobayashi E, Akiyama K, Kawai Y, Ozawa M, et al. (2004) Fine mapping of a region of rat chromosome 12 close to the aspermia (as) locus and comparison with the human orthologous regions. Exp Anim 53:429–435
Ochman H, Gerber AS, Hartl DL (1988) Genetic application of an inverse polymerase chain reaction. Genetics 120:621–623
Perry WL, Hustad CM, Swing DA, O’Sullivan TN, Jenkins NA, et al. (1998) The itchy locus encodes a novel ubiquitin protein ligase that is disrupted in a 18H mice. Nat Genet 18:143–146
Peters J, Tease C, Ball ST (1992) Koala, Koa, is associated with an inversion on mouse chromosome 15. Genet Res 59:237–238
Pitera JE, Smith VV, Thorogood P, Milla PJ (1999) Coordinated expression of 3′ Hox genes during murine embryonal gut development: an enteric Hox code. Gastroenterology 117:1339–1351
Rice R, Spencer-Dene B, Connor EC, Gritli-Linde A, McMahon AP, et al. (2004) Disruption of Fgf10/Fgfr2b-coordinated epithelial-mesenchymal interactions causes cleft palate. J Clin Invest 113:1692–1700
Roderick TH, Hawes NL, Hillyard AL (1996) Map of inversions. In: Lyon MF, Rastan S, Brown SDM, eds. Genetic variants and strains of the laboratory mouse, 3rd ed., (New York: Oxford University Press), pp 1524–1531
Satokata I, Maas R (1994) Msx1 deficient mice exhibit cleft palate and abnormalities of craniofacial and tooth development. Nat Genet 6:348–355
Shamblott MJ, Bugg EM, Lawler AM, Gearhart JD (2002) Craniofacial abnormalities resulting from targeted disruption of the murine Sim2 gene. Dev Dyn 224:373–380
Shinkai Y, Tsuji T, Kawamoto Y, Kunieda T (2004) New mutant mouse with skeletal deformities caused by mutation in delta like 3 (Dll3) gene. Exp Anim 53:129–136
Suemori H, Noguchi S (2000) HoxC cluster genes are dispensable for overall body plan of mouse embryonic development. Dev Biol 220:333–342
Wantia N, Rettinger G (2002) The current understanding of cleft lip malformations. Facial Plast Surg 18:147–153
Watanabe H, Kimata K, Line S, Strong D, Gao L-Y, et al. (1994) Mouse cartilage matrix deficiency (cmd) caused by a 7 bp deletion in the aggrecan gene. Nat Genet 7:154–157
Wilkie AOM, Morris-Kay GM (2001) Genetics of craniofacial development and malformation. Nat Rev Genet 2:458–468
Wise TL, Pravtcheva DD (2004) Oligosyndactylism mice have an inversion of chromosome 8. Genetics 168:2099–2112
Zákány J, Kmita M, Alarcon P, de la Pompa J-L, Duboule D (2001) Localized and transient transcription of Hox genes suggests a link between patterning and the segmentation clock. Cell 106:207–217
Zhao Y, Guo Y-J, Tomac AC, Taylor NR, Grinberg A, et al. (1999) Isolated cleft palate in mice with a targeted mutation of the LIM homeobox gene Lhx8. Proc Natl Acad Sci USA 96:15002–15006
Acknowledgments
The authors thank Dr. Yun You for sharing information on the Eh mice. This work was partly supported by the Sasakawa Scientific Research Grant from the Japan Science Society.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Katayama, K., Furuno, A., Akiyama, K. et al. Characterization of chromosomal inversion of the mouse hairy ears (Eh) mutation associated with cleft palate. Mamm Genome 18, 246–254 (2007). https://doi.org/10.1007/s00335-007-9015-7
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00335-007-9015-7