Characterization of a novel insertional mouse mutation, kkt:: A closely linked modifier of Pax1

被引:2
作者
Bialek, P [1 ]
Chan, CTJ
Yee, SP
机构
[1] Univ Western Ontario, Dept Biochem, London, ON, Canada
[2] Univ Western Ontario, Dept Oncol, London, ON, Canada
[3] London Reg Canc Ctr, Canc Res Labs, London, ON N6A 4L6, Canada
[4] Inst Child Hlth, London WC1N 1EH, England
关键词
transgenic; insertional mutant; skeletal abnormalities;
D O I
10.1006/dbio.1999.9584
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
We describe a novel transgene insertional mouse mutant with skeletal abnormalities characterized by a kinked tail and severe curvature of the spine. The disrupted locus is designated Wt for "kyphoscoliosis kinked tail." Malformed vertebrae including bilateral ossification centers and premature fusion of the vertebral body to the pedicles are observed along the vertebral column, and the lower thoracic and lumbar vertebrae are the most affected. Some of the homozygous Wt neonates displayed two backward-pointing transverse processes in the sixth lumbar vertebra (L6) that resembled the first sacral vertebra, and some displayed one forward- and one backward-pointing transverse process in L6. The fourth and fifth sternebrae were also fused, and the acromion process of the scapula was missing in kkt mice. The skeletal abnormalities are similar to those observed in the mouse mutant undulated (un). The transgene is integrated at the dis tal end of chromosome 2 close to the Pax1 gene, as revealed by FISH[ analysis. However, mutation of the Pax1 gene is responsible for the un phenotype, but the Pax1 gene in the kkt mice is not rearranged or deleted. Pax1 is expressed normally in Wt embryos and in the thymus of mature animals, and there is no mutation in its coding sequence. Thus, the skeletal abnormalities observed in the Wit mutant are not due to a lack of functional Pax1. Mouse genomic sequences flanking the transgene and PAC clones spanning the wild-type kkt locus have been isolated, and reverse Northern analysis showed that the PACs contain transcribed sequence. Compound heterozygotes between un and Wt (un(+/-)/kkt(+/-)) display skeletal abnormalities similar to those of un or kkt homozygotes, but they have multiple lumbar vertebrae with a split vertebral body that is more severe than in homozygous un or kkt neonates. Furthermore, the sternebrae are not fused and no backward-pointing transverse processes are detected in L6. It is therefore apparent that these two mutations do not fully complement each other, and we propose that a gene in the kkt locus possesses a unique role that functions in concert with Pax1 during skeletal development. (C) 2000 Academic Press.
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页码:354 / 366
页数:13
相关论文
共 55 条
[1]   Pax6 and Cdx2/3 form a functional complex on the rat glucagon gene promoter G1-element [J].
Andersen, FG ;
Heller, RS ;
Petersen, HV ;
Jensen, J ;
Madsen, OD ;
Serup, P .
FEBS LETTERS, 1999, 445 (2-3) :306-310
[2]  
[Anonymous], 1994, MANIPULATING MOUSE E
[3]  
Aubin J, 1998, DEV DYNAM, V212, P141, DOI 10.1002/(SICI)1097-0177(199805)212:1<141::AID-AJA13>3.0.CO
[4]  
2-A
[5]   UNDULATED, A MUTATION AFFECTING THE DEVELOPMENT OF THE MOUSE SKELETON, HAS A POINT MUTATION IN THE PAIRED BOX OF PAX-1 [J].
BALLING, R ;
DEUTSCH, U ;
GRUSS, P .
CELL, 1988, 55 (03) :531-535
[6]   GENETIC AND PHYSICAL INTERACTIONS BETWEEN SRP1P AND NUCLEAR-PORE COMPLEX PROTEINS NUP1P AND NUP2P [J].
BELANGER, KD ;
KENNA, MA ;
WEI, S ;
DAVIS, LI .
JOURNAL OF CELL BIOLOGY, 1994, 126 (03) :619-630
[7]   THE SUA8 SUPPRESSORS OF SACCHAROMYCES-CEREVISIAE ENCODE REPLACEMENTS OF CONSERVED RESIDUES WITHIN THE LARGEST SUBUNIT OF RNA POLYMERASE-II AND AFFECT TRANSCRIPTION START SITE SELECTION SIMILARLY TO SUA7 (TFIIB) MUTATIONS [J].
BERROTERAN, RW ;
WARE, DE ;
HAMPSEY, M .
MOLECULAR AND CELLULAR BIOLOGY, 1994, 14 (01) :226-237
[8]   THE MOUSE DYSTONIA MUSCULORUM GENE IS A NEURAL ISOFORM OF BULLOUS PEMPHIGOID ANTIGEN-1 [J].
BROWN, A ;
BERNIER, G ;
MATHIEU, M ;
ROSSANT, J ;
KOTHARY, R .
NATURE GENETICS, 1995, 10 (03) :301-306
[9]   MUTATION OF A NEW SODIUM-CHANNEL GENE, SCN8A, IN THE MOUSE MUTANT MOTOR END-PLATE DISEASE [J].
BURGESS, DL ;
KOHRMAN, DC ;
GALT, J ;
PLUMMER, NW ;
JONES, JM ;
SPEAR, B ;
MEISLER, MH .
NATURE GENETICS, 1995, 10 (04) :461-465
[10]   THE MOLECULAR-BASIS OF THE UNDULATED PAX-1 MUTATION [J].
CHALEPAKIS, G ;
FRITSCH, R ;
FICKENSCHER, H ;
DEUTSCH, U ;
GOULDING, M ;
GRUSS, P .
CELL, 1991, 66 (05) :873-884