QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

This Article Figures Only Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Hide, T. Articles by Matsuo, I. Search for Related Content PubMed PubMed Citation Articles by Hide, T. Articles by Matsuo, I. Social Bookmarking                         What's this?

Genetic modifiers of otocephalic phenotypes in Otx2 heterozygous mutant mice

Takuichiro Hide^1,2, Jun Hatakeyama¹, Chiharu Kimura-Yoshida^1,3, E Tian¹, Naoki Takeda⁴, Yukitaka Ushio², Toshihiko Shiroishi⁵, Shinichi Aizawa^1,3,*, and Isao Matsuo^1,3

Present address: Vertebrate Body Plan Group, RIKEN Center for Developmental Biology, 2-2-3 Minatojima Minami Cho, Chuou-Ku, Kobe, Hyougo 650-0047, Japan
¹ Department of Morphogenesis, Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University, Honjo 2-2-1, Kumamoto 860-0811, Japan
² Department of Neurosurgery, Kumamoto University School of Medicine, Kumamoto University, Honjo 2-2-1, Kumamoto 860-0811, Japan
³ Vertebrate Body Plan Group, RIKEN Center for Developmental Biology, 2-2-3 Minatojima Minami Cho, Chuou-Ku, Kobe, Hyougo 650-0047, Japan
⁴ Division of Transgenic Technology, Center for Animal Resources and Development (CARD), Kumamoto University, Honjo 2-2-1, Kumamoto 860-0811, Japan
⁵ Department of Mammalian Development, National Institute of Genetics, Mishima, Japan

*Author for correspondence (e-mail: saizawa{at}cdb.riken.go.jp)

Accepted 11 June 2002

Mice heterozygous for the Otx2 mutation display a craniofacial malformation, known as otocephaly or agnathia-holoprosencephaly complex. The severity of the phenotype is dependent on the genetic background of a C57BL/6 (B6) strain; most of the offspring of Otx2 knock-out chimeras, which are equivalent to the F₁ of CBA and B6 strains, backcrossed with B6 females display reduction or loss of mandible, whereas those backcrossed with CBA females do not show noticeable phenotype at birth. The availability of phenotypically disparate strains renders identification of Otx2 modifier loci possible. In this study, a backcross of chimera with B6 was generated and genome-wide scans were conducted with polymorphic markers for non-mendelian distribution of alleles in Otx2 heterozygous mutant mice displaying abnormalities in the lower jaw. We identified one significant locus, Otmf18, between D18Mit68 and D18Mit120 on chromosomes 18, linked to the mandibular phenotype (LOD score 3.33). A similar replication experiment using a second backcross (N3) mouse demonstrated the presence of another significant locus, Otmf2 between D2Mit164 and D2Mit282 on chromosome 2, linked to the mandibular phenotype (LOD score 3.93). These two modifiers account for the distribution of the craniofacial malformations by the genetic effect between B6 and CBA strains. Moreover, Otmf2 contain a candidate gene for several diseases in mice and humans. These genetic studies involving an otocephalic mouse model appear to provide new insights into mechanistic pathways of craniofacial development. Furthermore, these experiments offer a powerful approach with respect to identification and characterization of candidate genes that may contribute to human agnathia-holoprosencephaly complex diseases.

Key words: Otx2, Otocephaly, Agnathia-holoprosencephaly complex, Genetic modifier, Neural crest, Mandible, Mouse

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?