{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T05:55:15Z","timestamp":1791093315829,"version":"4.1.0"},"reference-count":75,"publisher":"The Company of Biologists","issue":"18","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2002,9,15]]},"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.1242\/dev.129.18.4347","type":"journal-article","created":{"date-parts":[[2021,4,25]],"date-time":"2021-04-25T09:19:29Z","timestamp":1619342369000},"page":"4347-4357","source":"Crossref","is-referenced-by-count":71,"title":["Genetic modifiers of otocephalic phenotypes in\n                    <i>Otx2<\/i>\n                    heterozygous mutant mice"],"prefix":"10.1242","volume":"129","author":[{"given":"Takuichiro","family":"Hide","sequence":"first","affiliation":[{"name":"Department of Morphogenesis, Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University, Honjo 2-2-1, Kumamoto 860-0811, Japan"},{"name":"Department of Neurosurgery, Kumamoto University School of Medicine, Kumamoto University, Honjo 2-2-1, Kumamoto 860-0811, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Hatakeyama","sequence":"additional","affiliation":[{"name":"Department of Morphogenesis, Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University, Honjo 2-2-1, Kumamoto 860-0811, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiharu","family":"Kimura-Yoshida","sequence":"additional","affiliation":[{"name":"Department of Morphogenesis, Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University, Honjo 2-2-1, Kumamoto 860-0811, Japan"},{"name":"Vertebrate Body Plan Group, RIKEN Center for Developmental Biology, 2-2-3 Minatojima Minami Cho, Chuou-Ku, Kobe, Hyougo 650-0047, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Morphogenesis, Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University, Honjo 2-2-1, Kumamoto 860-0811, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoki","family":"Takeda","sequence":"additional","affiliation":[{"name":"Division of Transgenic Technology, Center for Animal Resources and Development (CARD), Kumamoto University, Honjo 2-2-1, Kumamoto 860-0811, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukitaka","family":"Ushio","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Kumamoto University School of Medicine, Kumamoto University, Honjo 2-2-1, Kumamoto 860-0811, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshihiko","family":"Shiroishi","sequence":"additional","affiliation":[{"name":"Department of Mammalian Development, National Institute of Genetics, Mishima, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinichi","family":"Aizawa","sequence":"additional","affiliation":[{"name":"Department of Morphogenesis, Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University, Honjo 2-2-1, Kumamoto 860-0811, Japan"},{"name":"Vertebrate Body Plan Group, RIKEN Center for Developmental Biology, 2-2-3 Minatojima Minami Cho, Chuou-Ku, Kobe, Hyougo 650-0047, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isao","family":"Matsuo","sequence":"additional","affiliation":[{"name":"Department of Morphogenesis, Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University, Honjo 2-2-1, Kumamoto 860-0811, Japan"},{"name":"Vertebrate Body Plan Group, RIKEN Center for Developmental Biology, 2-2-3 Minatojima Minami Cho, Chuou-Ku, Kobe, Hyougo 650-0047, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042511380638600_ACAMPORA-ETAL-1995","doi-asserted-by":"crossref","unstructured":"Acampora, D., Mazan, S., Lallemand, Y., Avantaggiato, V., Maury, M., Simeone, A. and Bru\u0302let, P. (1995). Forebrain and midbrain regions are deleted in Otx2\u2013\/\u2013 mutants due to a defective anterior neuroectoderm specification during gastrulation. Development121, 3279-3290.","DOI":"10.1242\/dev.121.10.3279"},{"key":"2021042511380638600_ACAMPORA-ETAL-1997","doi-asserted-by":"crossref","unstructured":"Acampora, D., Avantaggiato, V., Tuorto, F. and Simeone, A. (1997). Genetic control of brain morphogenesis through Otx gene dosage requirement. Development124, 3639-3650.","DOI":"10.1242\/dev.124.18.3639"},{"key":"2021042511380638600_ACAMPORA-ETAL-1998","doi-asserted-by":"crossref","unstructured":"Acampora, D., Avantaggiato, V., Tuorto, F., Briata, P., Corte, G. and Simeone, A. (1998). Visceral endoderm-restricted translation of Otx1 mediates recovery of Otx2 requirements for specification of anterior neural plate and normal gastrulation. Development125, 5091-5104.","DOI":"10.1242\/dev.125.24.5091"},{"key":"2021042511380638600_ANG-ETAL-1994","doi-asserted-by":"crossref","unstructured":"Ang, S. L., Conlon, R. A., Jin, O. and Rossant, J. (1994). Positive and negative signals from mesoderm regulate the expression of mouse Otx2 in ectoderm explants. Development120, 2979-2989.","DOI":"10.1242\/dev.120.10.2979"},{"key":"2021042511380638600_ANG-ETAL-1996","doi-asserted-by":"crossref","unstructured":"Ang, S.-L., Jin, O., Rhinn, M., Daigle, N., Stevenson, L. and Rossant, J. (1996). A targeted mouse Otx2 mutation leads to severe defects in gastrulation and formation of axial mesoderm and to deletion of rostral brain. Development122, 243-252.","DOI":"10.1242\/dev.122.1.243"},{"key":"2021042511380638600_BASTEN-ETAL-2001","unstructured":"Basten, C. J., Weir, B. S. and Zeng, Z.-B. (2001). QTL Cartographer: A reference manual and tutorial for QTL mapping. Program in Statistical Genetics, Department of Statistics, North Carolina State University."},{"key":"2021042511380638600_BERGE-ETAL-1998A","doi-asserted-by":"crossref","unstructured":"Berge, D. t., Brouwer, A., Korving, J., Martin, J. F. and Meijlink, F. (1998a). Prx1 and Prx2 in skeletogenesis: roles in the craniofacial region, inner ear and limbs. Development125, 3831-3842.","DOI":"10.1242\/dev.125.19.3831"},{"key":"2021042511380638600_BERGE-ETAL-1998B","doi-asserted-by":"crossref","unstructured":"Berge, D. t., Brouwer, A., Bahi, S. E., Guenet, J.-L., Robert, B. and Meijlink, F. (1998b). Mouse Alx3: An aristaless-like homeobox gene expressed during embryogenesis in ectomesenchyme and lateral plate mesoderm. Dev. Biol.199, 11-25.","DOI":"10.1006\/dbio.1998.8921"},{"key":"2021042511380638600_BIXLER-ETAL-1985","unstructured":"Bixler, D., Ward, R. and Gale, D. D. (1985). Agnathia-holoprosencephaly: a developmental field complex involving face and brain. Report of 3 cases. J. Craniofac. Genet. Dev. Biol.Suppl. 1, 241-249."},{"key":"2021042511380638600_BROWN-ETAL-1998","doi-asserted-by":"crossref","unstructured":"Brown, S. A., Warburton, D., Brown, L. Y., Yu, C. Y., Roeder, E. R., Stengel-Rutkowski, S., Hennekam, R. C. and Muenke, M. (1998). Holoprosencephaly due to mutations in ZIC2, a homologue of Drosophila odd-paired. Nat. Genet.20, 180-183.","DOI":"10.1038\/2484"},{"key":"2021042511380638600_CAI-1998","doi-asserted-by":"crossref","unstructured":"Cai, R. L. (1998). Human CART1, a paired-class homeodomain protein, activates transcription through palindromic binding sites. Biochem. Bioph. Res. Comm.250, 305-311.","DOI":"10.1006\/bbrc.1998.9257"},{"key":"2021042511380638600_COULY-ETAL-1993","doi-asserted-by":"crossref","unstructured":"Couly, G. F., Coltey, P. M. and le Douarin, N. M. (1993). The triple origin of skull in higher vertebrates: a study in quail-chick chimeras. Development117, 409-429.","DOI":"10.1242\/dev.117.2.409"},{"key":"2021042511380638600_CSERJESI-ETAL-1992","doi-asserted-by":"crossref","unstructured":"Cserjesi, P., Lilly, B., Bryson, L., Wang, Y., Sassoon, D. A. and Olson, E. N. (1992). MHox: a mesodermally restricted homeodomain protein that binds an essential site in the muscle creatine kinase enhancer. Development115, 1087-1101.","DOI":"10.1242\/dev.115.4.1087"},{"key":"2021042511380638600_DARVASI-1998","doi-asserted-by":"crossref","unstructured":"Darvasi, A. (1998). Experimental strategies for the genetic dissection of complex traits in animal models. Nat. Genet.18, 19-24.","DOI":"10.1038\/ng0198-19"},{"key":"2021042511380638600_DATTANI-ETAL-1998","doi-asserted-by":"crossref","unstructured":"Dattani, M. T., Martinez-Barbera, J. P., Thomas, P. Q., Brickman, J. M., Gupta, R., Martensson, I.-L., Toresson, H., Fox, M., Wales, J. K. H., Hindmarsh, P. C. et al. (1998). Mutations in the homeobox gene HESX1\/Hesx1 associated with septo-optic dysplasia in human and mouse. Nat. Genet.19, 125-133.","DOI":"10.1038\/477"},{"key":"2021042511380638600_DIETRICH-ETAL-1992","doi-asserted-by":"crossref","unstructured":"Dietrich, W., Katz, H., Lincoln, S. E., Shin, H.-S., Friedman, J., Dracopoli, N. C. and Lander, E. S. (1992). A genetic map of the mouse suitable for typing intraspecific crosses. Genetics131, 423-447.","DOI":"10.1093\/genetics\/131.2.423"},{"key":"2021042511380638600_DIETRICH-ETAL-1994","doi-asserted-by":"crossref","unstructured":"Dietrich, W. F., Miller., J. C., Steen, R. G., Merchant, M., Damron, D., NAhf, R., Gross, A., Joyce, D. C., Wessel, M., Dredge, R. D. et al. (1994). A genetic map of the mouse with 4,006 simple sequence length polymorphisms. Nat. Genet.7, 220-245.","DOI":"10.1038\/ng0694supp-220"},{"key":"2021042511380638600_FALLER-AND-ROSSIER-1969","unstructured":"Faller, A. and Rossier, B. (1969). Reconstruction of brain and ventricle system in an anchyote prosophthalmic otocephalic newborn cephalothoracopagus rabbit. Acta Anat.73,2-31."},{"key":"2021042511380638600_FORSTHOEFEL-1962","doi-asserted-by":"crossref","unstructured":"Forsthoefel, P. F. (1962). Genetics and manifold effects of Strong\u2019s luxoid gene in the mouse, including its interactions with Green\u2019s luxoid and Carter\u2019s luxate genes. J. Morphol.110, 391-420.","DOI":"10.1002\/jmor.1051100306"},{"key":"2021042511380638600_FORSTHOEFEL-1968","doi-asserted-by":"crossref","unstructured":"Forsthoefel, P. F. (1968). Responses to selection for plus and minus modifiers of some effects of Strong\u2019s luxoid gene on the mouse skeleton. Teratology1, 339-51.","DOI":"10.1002\/tera.1420010311"},{"key":"2021042511380638600_GRIPP-ETAL-2000","doi-asserted-by":"crossref","unstructured":"Gripp, K. W., Wotton, D., Edwards, M. C., Roessler, E., Ades, L., Meinecke, P., Richieri-Costa, A., Zackai, E. H., Massague, J., Muenke, M. and Elledge, S. J. (2000). Mutations in TGIF cause holoprosencephaly and link NODAL signalling to human neural axis determination. Nat. Genet.25, 205-208.","DOI":"10.1038\/76074"},{"key":"2021042511380638600_HORAN-ETAL-1995","doi-asserted-by":"crossref","unstructured":"Horan, G. S. B., Kovacs, E. N., Behringer, R. R. and Featherstone, M. S. (1995). Mutations in paralogous Hox genes result in overlapping homeotic transformations of the axial skeleton: evidence for unique and redundant function. Dev. Biol.169, 359-372.","DOI":"10.1006\/dbio.1995.1150"},{"key":"2021042511380638600_IMAI-ETAL-1996","doi-asserted-by":"crossref","unstructured":"Imai, H., Osumi-Yamashita, N., Ninomiya, Y. and Eto, K. (1996). Contribution of early-emigrating midbrain crest cells to the dental mesenchyme of mandibular molar teeth in rat embryos. Dev. Biol.176, 151-165.","DOI":"10.1006\/dbio.1996.9985"},{"key":"2021042511380638600_JIANG-AND-ZENG-1995","doi-asserted-by":"crossref","unstructured":"Jiang, C. and Zeng, Z.-B. (1995) Multiple trait analysis of genetic mapping for quantitative trait loci. Genetics140, 1111-1127.","DOI":"10.1093\/genetics\/140.3.1111"},{"key":"2021042511380638600_JURILOFF-ETAL-1985","unstructured":"Juriloff, D. M., Sulik, K. K., Roderick, T. H. and Hogan, B. K. (1985). Genetic and developmental studies of a new mouse mutation that produces otocephaly. J. Craniofac. Genet. Dev. Biol.5, 121-145."},{"key":"2021042511380638600_KELLY-AND-BRYDEN-1983","doi-asserted-by":"crossref","unstructured":"Kelly, W. L. and Bryden, M. M. (1983). A modified differential stain for cartilage and bone in whole mount preparations of mammalian fetuses and small vertebrates. Stain Technol.58,131-134.","DOI":"10.3109\/10520298309066773"},{"key":"2021042511380638600_KIMURA-ETAL-1997","doi-asserted-by":"crossref","unstructured":"Kimura, C., Takeda, N., Suzuki, M., Oshimura, M., Aizawa, S. and Matsuo, I. (1997). Cis-acting elements conserved between mouse and pufferfish Otx2 genes govern the expression in mesencephalic neural crest cells. Development124, 3929-3941.","DOI":"10.1242\/dev.124.20.3929"},{"key":"2021042511380638600_KIMURA-ETAL-2000","doi-asserted-by":"crossref","unstructured":"Kimura, C., Yoshinaga, K., Tian, E., Suzuki, M., Aizawa, S. and Matsuo, I. (2000). Visceral endoderm mediates forebrain development by suppressing posteriorizing signals. Dev. Biol.225, 304-321.","DOI":"10.1006\/dbio.2000.9835"},{"key":"2021042511380638600_KIMURA-ETAL-2001","doi-asserted-by":"crossref","unstructured":"Kimura, C., Shen, M. M., Takeda, N., Aizawa, S. and Matsuo, I. (2001). Complementary functions of Otx2 and Cripto in initial patterning of mouse epiblast. Dev. Biol.235, 12-32.","DOI":"10.1006\/dbio.2001.0289"},{"key":"2021042511380638600_KOENTGES-AND-LUMSDEN-1996","doi-asserted-by":"crossref","unstructured":"Koentges, G. and Lumsden, A. (1996). Rhombencephalic neural crest segmentation is preserved throughout craniofacial ontogeny. Development122, 3229-3242.","DOI":"10.1242\/dev.122.10.3229"},{"key":"2021042511380638600_LANDER-AND-BOTSTEIN-1989","doi-asserted-by":"crossref","unstructured":"Lander, E. S. and Botstein, D. (1989). Mapping mendelian factors underlying quantitative traits using RFLP linkage maps. Genetics121, 185-199.","DOI":"10.1093\/genetics\/121.1.185"},{"key":"2021042511380638600_LANDER-AND-SCHORK-1994","doi-asserted-by":"crossref","unstructured":"Lander, E. S. and Schork, N. J. (1994). Genetic dissection of complex traits. Science265, 2037-2048.","DOI":"10.1126\/science.8091226"},{"key":"2021042511380638600_LANDER-AND-KRUGLYAK-1995","doi-asserted-by":"crossref","unstructured":"Lander, E. and Kruglyak, L. (1995). Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat. Genet.11, 241-247.","DOI":"10.1038\/ng1195-241"},{"key":"2021042511380638600_LECOUTER-ETAL-1998","doi-asserted-by":"crossref","unstructured":"LeCouter, J. E., Kablar, B., Whyte, P. F. M., Ying, C. and Rudnicki, M. A. (1998). Strain-dependent embryonic lethality in mice lacking the retinoblastoma-related p130 gene. Development125, 4669-4679.","DOI":"10.1242\/dev.125.23.4669"},{"key":"2021042511380638600_LE-DOUARIN-1982","unstructured":"Le Douarin, N. (1982). The neural crest. In Development and Cell Biology Series 12. Cambridge: Cambridge University Press."},{"key":"2021042511380638600_LIEM-ETAL-1995","doi-asserted-by":"crossref","unstructured":"Liem, K. F., Jr, Tremml, G., Roelink, H. and Jessell, T. M. (1995). Dorsal differentiation of neural plate cells induced by BMP-mediated signals from epidermal ectoderm. Cell82, 969-979.","DOI":"10.1016\/0092-8674(95)90276-7"},{"key":"2021042511380638600_LOVE-ETAL-1990","doi-asserted-by":"crossref","unstructured":"Love, J. M., Knight, A. M., McAleer, M. A. and Todd, J. A. (1990). Towards construction of a high resolution map of the mouse genome using PCR-analyzed microsatellites. Nucleic Acids Res. 18, 4123-4130.","DOI":"10.1093\/nar\/18.14.4123"},{"key":"2021042511380638600_LU-ETAL-1999","doi-asserted-by":"crossref","unstructured":"Lu, M.-F., Cheng, H.-T., Kern, M. J., Potter, S. S., Tran, B., Diekwisch, T. G. H. and Martin, J. F. (1999). prx-1 functions cooperatively with another paired-related homeobox gene, prx-2, to maintain cell fates within the craniofacial mesenchyme. Development126, 495-504.","DOI":"10.1242\/dev.126.3.495"},{"key":"2021042511380638600_MATSUNAGA-AND-SHIOTA-1977","doi-asserted-by":"crossref","unstructured":"Matsunaga, E. and Shiota, K. (1977). Holoprosencephaly in human embryos: Epidemiologic studies of 150 cases. Teratology16, 261-272.","DOI":"10.1002\/tera.1420160304"},{"key":"2021042511380638600_MATSUO-ETAL-1995","doi-asserted-by":"crossref","unstructured":"Matsuo, I., Kuratani, S., Kimura, C., Takeda, N. and Aizawa, S. (1995). Mouse Otx2 functions in the formation and patterning of rostral head. Genes Dev.9, 2646-2658.","DOI":"10.1101\/gad.9.21.2646"},{"key":"2021042511380638600_MAVROGIANNIS-ETAL-2001","doi-asserted-by":"crossref","unstructured":"Mavrogiannis, L. A., Antonopoulou, I., Baxova, A., Kutilek, S., Kim, C. A., Sugayama, S. M., Salamanca, A., Wall, S. A., Morris-Kay, G. M. and Wilkie, A. O. M. (2001). Haploinsufficiency of the human homeobox gene ALX4 causes skull ossification defects. Nat. Genet.27, 17-18.","DOI":"10.1038\/83703"},{"key":"2021042511380638600_NANNI-ETAL-1999","doi-asserted-by":"crossref","unstructured":"Nanni, L., Ming, J. E., Bocian, M., Steinhaus, K., Bianchi, D. W., Die-Smulders, C., Giannotti, A., Imaizumi, K., Jones, K. L., Campo, M. D. et al. (1999). The mutational spectrum of the Sonic hedgehog gene in holoprosencephaly: SHH mutations cause a significant proportion of autosomal dominant holoprosencephaly. Hum. Mol. Genet.8, 2479-2488.","DOI":"10.1093\/hmg\/8.13.2479"},{"key":"2021042511380638600_OPITZ-1980","doi-asserted-by":"crossref","unstructured":"Opitz, J. M. (1980). Letter to the editors. Clin. Genet.17, 69-71.","DOI":"10.1111\/j.1399-0004.1980.tb00139.x"},{"key":"2021042511380638600_OSUMI-YAMASHITA-ETAL-1994","doi-asserted-by":"crossref","unstructured":"Osumi-Yamashita, N., Ninomiya, Y., Doi, H. and Eto, K. (1994). The contribution of both forebrain and midbrain crest cells to the mesenchyme in the frontonasal mass of mouse embryos. Dev. Biol.164, 409-419.","DOI":"10.1006\/dbio.1994.1211"},{"key":"2021042511380638600_PAULI-ETAL-1983","doi-asserted-by":"crossref","unstructured":"Pauli, R. M., Pettersen, J. C., Arya, S. and Gilbert, E. F. (1983). Familial agnathia-holoprosencephaly. Am. J. Med. Genet.14, 677-698.","DOI":"10.1002\/ajmg.1320140411"},{"key":"2021042511380638600_PROETZEL-ETAL-1995","doi-asserted-by":"crossref","unstructured":"Proetzel, G., Pawlowski, S. A., Wiles, M. V., Yin, M., Boivin, G. P., Howles, P. N., Ding, J., Ferguson, M. W. J. and Doetschman, T. (1995). Transforming growth factor-\u03b23 is required for secondary palate fusion. Nat. Genet.11, 409-414.","DOI":"10.1038\/ng1295-409"},{"key":"2021042511380638600_QU-ETAL-1997","unstructured":"Qu, S., Li, L. and Wisdom, R. (1997). Alx4:cDNA cloning and characterization of a novel paired-type homeodomain protein. Gene203, 217-223."},{"key":"2021042511380638600_QU-ETAL-1998","doi-asserted-by":"crossref","unstructured":"Qu, S., Tucker, S. C., Ehrlich, J. S., Levorse, J. M., Flaherty, L. A., Wisdom, R. and Vogt, T. F. (1998). Mutations in mouse Aristaless-like4 cause Strong\u2019s luxoid polydactyly. Development125, 2711-2721.","DOI":"10.1242\/dev.125.14.2711"},{"key":"2021042511380638600_QU-ETAL-1999","doi-asserted-by":"crossref","unstructured":"Qu, S., Tucker, S. C., Zhao, Q., deCrombrugghe, B. and Wisdom, R. (1999). Physical and genetic interactions between Alx4 and Cart1. Development126, 359-369.","DOI":"10.1242\/dev.126.2.359"},{"key":"2021042511380638600_ROESSLER-ETAL-1996","doi-asserted-by":"crossref","unstructured":"Roessler, E., Belloni, E., Gaudenz, K., Jay, P., Berta, P., Scherer, S. W., Tsui, L. C. and Muenke, M. (1996). Mutations in the human Sonic Hedgehog gene cause holoprosencephaly. Nat. Genet.14, 357-360.","DOI":"10.1038\/ng1196-357"},{"key":"2021042511380638600_ROZMAHEL-ETAL-1996","doi-asserted-by":"crossref","unstructured":"Rozmahel, R., Wilschanski, M., Matin, A., Plyte, S., Oliver, M., Auerbach, W., Moore, A., Forstner, J., Durie, P., Nadeau, J., Bear, C. and Tsui, L.-C. (1996). Modulation of disease severity in cystic fibrosis transmembrane conductance regulator deficient mice by a secondary genetic factor. Nat. Genet.12, 280-287.","DOI":"10.1038\/ng0396-280"},{"key":"2021042511380638600_SAMBROOK-ETAL-1989","unstructured":"Sambrook, J., Fritsch, E. F. and Maniatis, T. (1989). Molecular Cloning: A Laboratory Manual, 2nd edn. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press."},{"key":"2021042511380638600_SELLECK-AND-BRONNER-FRASER-1995","doi-asserted-by":"crossref","unstructured":"Selleck, M. A. and Bronner-Fraser, M. (1995). Origins of the avian neural crest: the role of neural plate-epidermal interactions. Development121, 525-538.","DOI":"10.1242\/dev.121.2.525"},{"key":"2021042511380638600_SIMEONE-ETAL-1992","doi-asserted-by":"crossref","unstructured":"Simeone, A., Acampora, D., Gulisano, M., Stornaiuolo, A. and Boncinelli, E. (1992). Nested expression domains of four homeobox genes in developing rostral brain. Nature358, 687-690.","DOI":"10.1038\/358687a0"},{"key":"2021042511380638600_SIMEONE-ETAL-1993","doi-asserted-by":"crossref","unstructured":"Simeone, A., Acampora, D., Mallamaci, A., Stornaiuolo, A., D\u2019Apice, M. R., Nigro, V. and Boncinelli, E. (1993). A vertebrate gene related to orthodenticle contains a homeodomain of the bicoid class and demarcates anterior neuroectoderm in the gastrulating mouse embryo. EMBO J.12, 2735-2747.","DOI":"10.1002\/j.1460-2075.1993.tb05935.x"},{"key":"2021042511380638600_SMITH-1968","doi-asserted-by":"crossref","unstructured":"Smith, I. D. (1968). Agnathia and micrognathia in the sheep. Aust. Vet. J.44, 510-511.","DOI":"10.1111\/j.1751-0813.1968.tb09000.x"},{"key":"2021042511380638600_SUDA-ETAL-1996","doi-asserted-by":"crossref","unstructured":"Suda, Y., Matsuo, I., Kuratani, S. and Aizawa, S. (1996). Otx1 function overlaps with Otx2 in development of mouse forebrain and midbrain. Genes Cells1, 1031-1044.","DOI":"10.1046\/j.1365-2443.1996.900288.x"},{"key":"2021042511380638600_SUDA-ETAL-1997","doi-asserted-by":"crossref","unstructured":"Suda, Y., Matsuo, I. and Aizawa, S. (1997). Cooperation between Otx1 and Otx2 genes in developmental patterning of rostral brain. Mech. Dev.69, 125-141.","DOI":"10.1016\/S0925-4773(97)00161-5"},{"key":"2021042511380638600_SUDA-ETAL-2001","unstructured":"Suda, Y., Hossain, Z. M., Kobayashi, C., Hatano, O., Yoshida, M., Matsuo, I. and Aizawa, S. (2001). Emx2 directs the development of diencephalon in cooperation with Otx2. Development128, 2433-2450."},{"key":"2021042511380638600_TIAN-ETAL-2002","doi-asserted-by":"crossref","unstructured":"Tian, E, Kimura, C., Takeda, N., Aizawa, S. and Matsuo, I. (2002). Otx2 is required to respond to signals from anterior neural ridge for forebrain specification. Dev. Biol.242, 204-223.","DOI":"10.1006\/dbio.2001.0531"},{"key":"2021042511380638600_WALLIS-AND-MUENKE-1999","doi-asserted-by":"crossref","unstructured":"Wallis, D. E. and Muenke, M. (1999). Molecular mechanisms of holoprosencephaly. Mol. Genet. Metab.68, 126-138.","DOI":"10.1006\/mgme.1999.2895"},{"key":"2021042511380638600_WALLIS-AND-MUENKE-2000","doi-asserted-by":"crossref","unstructured":"Wallis, D. E. and Muenke, M. (2000). Mutations in holoprosencephaly. Hum. Mutat.16, 99-108.","DOI":"10.1002\/1098-1004(200008)16:2<99::AID-HUMU2>3.0.CO;2-0"},{"key":"2021042511380638600_WALLIS-ETAL-1999","doi-asserted-by":"crossref","unstructured":"Wallis, D. E., Roessler, E., Hehr, U., Nanni, L., Wiltshire, T., Richieri-Costa, A., Gillessen-Kaesbach, G., Zackai, E. H., Rommens, J. and Muenke, M. (1999). Mutations in the homeodomain of the human SIX3 gene cause holoprosencephaly. Nat. Genet.22, 196-198.","DOI":"10.1038\/9718"},{"key":"2021042511380638600_WAWERSIK-ETAL-1999","doi-asserted-by":"crossref","unstructured":"Wawersik, S., Purcell, P., Rauchman, M., Dudley, A. T., Robertson, E. J. and Maas, R. (1999). BMP7 acts in murine lens placode development. Dev. Biol.207, 176-188.","DOI":"10.1006\/dbio.1998.9153"},{"key":"2021042511380638600_WILLSON-1966","unstructured":"Willson, J. E. (1966). Congenital otocephalus in a lamb. Vet. Med. Small Anim. Clin.61, 58-59."},{"key":"2021042511380638600_WINTER-1996","unstructured":"Winter, R. M. (1996). What\u2019s in a face? Nat. Genet.12, 124-129."},{"key":"2021042511380638600_WOJNOWSKI-ETAL-1998","doi-asserted-by":"crossref","unstructured":"Wojnowski, L., Stancato, L. F., Zimmer, A. M., Hahn, H., Beck, T. W., Larner, A. C., Rapp, U. R. and Zimmer, A. (1998). Craf-1 protein kinase is essential for mouse development. Mech. Dev.76, 141-149.","DOI":"10.1016\/S0925-4773(98)00111-7"},{"key":"2021042511380638600_WRIGHT-AND-WAGNER-1934","doi-asserted-by":"crossref","unstructured":"Wright, S. and Wagner, K. (1934). Types of subnormal development of the head from inbred strains of guinea pigs and their bearing on the classification and interpretation of vertebrate monsters. Am. J. Anat.54, 383-447.","DOI":"10.1002\/aja.1000540303"},{"key":"2021042511380638600_WU-ETAL-2000","unstructured":"Wu, Y. Q., Badano, J. L., McCaskill, C., Vogel, H., Potocki, L. and Shaffer, L. G. (2000). Haploinsufficiency of ALX4 as a potential cause of parietal foramina in the 11p11.2 contiguous gene-deletion syndrome. Am. J. Hum. Genet.67, 1327-1332."},{"key":"2021042511380638600_WUYTS-ETAL-2000","doi-asserted-by":"crossref","unstructured":"Wuyts, W., Cleiren, E., Homfray, T., Rasore-Quartino, A., Vanhoenacker, F. and van Hul, W. (2000). The ALX4 homeobox gene is mutated in patients with ossification defects of the skull (foramina parietalia permagna, OMIM 168500). J. Med. Genet.37, 916-920.","DOI":"10.1136\/jmg.37.12.916"},{"key":"2021042511380638600_YAGI-ETAL-1993","doi-asserted-by":"crossref","unstructured":"Yagi, T., Tokunaga, T., Furuta, Y., Nada, S., Yoshida, M., Tsukada, T., Saga, Y., Takeda, N., Ikawa, Y. and Aizawa, S. (1993). A novel ES cell line, TT2, with high germline-differentiating potency. Anal. Biochem.214, 70-76.","DOI":"10.1006\/abio.1993.1458"},{"key":"2021042511380638600_ZENG-1994","doi-asserted-by":"crossref","unstructured":"Zeng, Z.-B. (1994). Precision mapping of quantitative trait loci. Genetics136, 1457-1468.","DOI":"10.1093\/genetics\/136.4.1457"},{"key":"2021042511380638600_ZHAO-ETAL-1994","doi-asserted-by":"crossref","unstructured":"Zhao, G.-Q., Eberspaecher, H., Seldin, M. F. and de Crombrugghe, B. (1994). The gene for homeodomain-containing protein Cart-1 is expressed in cells that have a chondrogenic potential during embryonic development. Mech. Dev.48, 245-254.","DOI":"10.1016\/0925-4773(94)90063-9"},{"key":"2021042511380638600_ZHAO-ETAL-1996","doi-asserted-by":"crossref","unstructured":"Zhao, Q., Behringer, R. R. and de Crombrugghe, B. (1996). Prenatal folic acid treatment suppresses acrania and meroanencephaly in mice mutant for the Cart1 homeobox gene. Nat. Genet.13, 275-283.","DOI":"10.1038\/ng0796-275"},{"key":"2021042511380638600_ZOLTEWICZ-ETAL-1999","doi-asserted-by":"crossref","unstructured":"Zoltewicz, J. S., Plummer, N. W., Lin, M. I. and Peterson, A. S. (1999). oto is a homeotic locus with a role in anteroposterior development that is partially redundant with Lim1. Development126, 5085-5095.","DOI":"10.1242\/dev.126.22.5085"}],"container-title":["Development"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/129\/18\/4347\/1140150\/4347.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/129\/18\/4347\/1140150\/4347.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,25]],"date-time":"2022-12-25T06:27:46Z","timestamp":1671949666000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dev\/article\/129\/18\/4347\/17885\/Genetic-modifiers-of-otocephalic-phenotypes-in"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2002,9,15]]},"references-count":75,"journal-issue":{"issue":"18","published-print":{"date-parts":[[2002,9,15]]}},"URL":"https:\/\/doi.org\/10.1242\/dev.129.18.4347","relation":{},"ISSN":["1477-9129","0950-1991"],"issn-type":[{"value":"1477-9129","type":"electronic"},{"value":"0950-1991","type":"print"}],"subject":[],"published":{"date-parts":[[2002,9,15]]}}}