title: Targeted ablation of the murine alpha-tropomyosin gene.
abstract: We created a mouse that lacks a functional alpha-tropomyosin gene using gene targeting in embryonic stem cells and blastocyst-mediated transgenesis. Homozygous alpha-tropomyosin "knockout" mice die between embryonic day 9.5 and 13.5 and lack alpha-tropomyosin mRNA. Heterozygous alpha-tropomyosin knockout mice have approximately 50% as much cardiac alpha-tropomyosin mRNA as wild-type littermates but similar alpha-tropomyosin protein levels. Cardiac gross morphology, histology, and function (assessed by working heart preparations) of heterozygous alpha-tropomyosin knockout and wild-type mice were indistinguishable. Mechanical performance of skinned papillary muscle strips derived from mutant and wild-type hearts also revealed no differences. We conclude that haploinsufficiency of the alpha-tropomyosin gene produces little or no change in cardiac function or structure, whereas total alpha-tropomyosin deficiency is incompatible with life. These findings imply that in heterozygotes there is a regulatory mechanism that maintains the level of myofibrillar tropomyosin despite the reduction in alpha-tropomyosin mRNA.
authors.affiliation: Howard Hughes Medical Institute, Boston, Mass., USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Blanchard
authors.forename: K
authors.initials: K
authors.lastname: Iizuka
authors.forename: M
authors.initials: M
authors.lastname: Christe
authors.forename: D A
authors.initials: DA
authors.lastname: Conner
authors.forename: A
authors.initials: A
authors.lastname: Geisterfer-Lowrance
authors.forename: F J
authors.initials: FJ
authors.lastname: Schoen
authors.forename: D W
authors.initials: DW
authors.lastname: Maughan
authors.forename: C E
authors.initials: CE
authors.lastname: Seidman
authors.forename: J G
authors.initials: JG
authors.lastname: Seidman
mesh_terms: D000818:Animals; D018390:Gene Targeting; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000473:pathology; D014335:Tropomyosin / Q000235:genetics* / Q000502:physiology
chemical_list: D014335:Tropomyosin