title: exma: an X-linked insertional mutation that disrupts forebrain and eye development.
abstract: Formation of the neural tube plays a primary role in establishing the body plan of the vertebrate embryo. Here we describe the phenotype and physical mapping of a highly penetrant X-linked male-lethal murine mutation, exma (exencephaly, microphthalmia/anophthalmia), that specifically disrupts development of the rostral neural tube and eye. The mutation arose from the random insertion of a transgene into the mouse X Chromosome (Chr). Eighty-three percent of transgenic male embryos display an open, disorganized forebrain and lack optic vesicles. No transgenic males survive beyond birth. Hemizygous females show a variable phenotype, including reduced viability and occasional exencephaly and/or microphthalmia. Altered or reduced expression patterns of Otx2, Pax6, Six3, and Mrx, known markers of early forebrain and eye development, confirmed the highly disorganized structure of the forebrain and lack of eye development in affected exma male embryos. Physical mapping of the transgene by FISH localized a single insertion site to the interval between Dmd and Zfx on the X Chr. A 1-Mb contig of BAC clones was assembled by using sequences flanking the transgene and revealed that the insertion lies close to Pola1 and Arx, a gene encoding a highly conserved homeobox protein known to be expressed in the developing forebrain of the mouse. Data from Southern blots of normal and transgenic DNA demonstrated that a large segment of DNA encompassing Arx and including part of Pola1 was duplicated as a result of the transgene insertion. From the physical mapping results, we propose a model of the gross rearrangements that accompanied transgene integration and discuss its implications for evaluating candidate genes for exma.
authors.affiliation: Division of Human and Molecular Genetics, Dept. of Pediatrics and Children's Research Institute, The Ohio State University, Children's Research Institute, 700 Children's Drive, Rm. 403, Columbus, Ohio 43205, USA.
authors.forename: David
authors.initials: D
authors.lastname: Cunningham
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xiao
authors.forename: Aurobindo
authors.initials: A
authors.lastname: Chatterjee
authors.forename: Kathleen
authors.initials: K
authors.lastname: Sulik
authors.forename: Diana
authors.initials: D
authors.lastname: Juriloff
authors.forename: Frederick
authors.initials: F
authors.lastname: Elder
authors.forename: Wilbur
authors.initials: W
authors.lastname: Harrison
authors.forename: Gabriele
authors.initials: G
authors.lastname: Schuster
authors.forename: Paul A
authors.initials: PA
authors.lastname: Overbeek
authors.forename: Gail E
authors.initials: GE
authors.lastname: Herman
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000853:Anophthalmos / Q000196:embryology / Q000235:genetics*; D020440:Gene Duplication; D008040:Genetic Linkage; D008297:Male; D051379:Mice; D016254:Mutagenesis, Insertional; D009154:Mutation; D009436:Neural Tube Defects / Q000196:embryology / Q000235:genetics*; D020161:Physical Chromosome Mapping; D014960:X Chromosome