Mouse zeta- and alpha-globin genes: embryonic survival, alpha-thalassemia, and genetic background effects.
A classical notion regarding the expression of murine embryonic zeta- and adult alpha-globin genes holds that there is a switch in globin production from the embryonic to the adult form during fetal development. Our previous in situ hybridization studies challenged this view, since both zeta- and alpha-globin mRNAs can be detected simultaneously in the earliest erythrocyte populations. This finding raises the possibility that zeta-globin production might be wholly or partially redundant in embryos in which the adult alpha-globin is also expressed. To test this possibility, we created a null mutation of the zeta-globin gene using homologous recombination in embryonic stem cells. Many outbred mice homozygous for the zeta-null mutation were able to develop normally, undermining the notion that there is an absolute need for zeta-globin and indicating that alpha-globin alone can serve the survival needs of the fetus. Interestingly, insertion of the PGK-Neo cassette (used to create the null mutation) into the zeta-globin gene appears to influence the expression of the nearby alpha-globin genes, giving rise to reduced alpha-globin production and to an alpha-thalassemia-like syndrome. There is also evidence indicating the strong influence of genetic background on the zeta-null and alpha1-null phenotypes, both of which are much more severe in the 129/SvEv inbred genetic background. These quantitative differences can potentially be exploited to identify genes important for erythropoiesis.
Leder
A
A
Department of Genetics, Harvard Medical School, Howard Hughes Medical Institute, Boston, MA 02115, USA.
Daugherty
C
C
Whitney
B
B
Leder
P
P
D000483:Alleles; D000818:Animals; D005314:Embryonic and Fetal Development / Q000235:genetics*; D004843:Epistasis, Genetic; D004920:Erythropoiesis / Q000235:genetics*; D005312:Fetal Blood / Q000737:chemistry*; D005313:Fetal Death / Q000097:blood / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D005838:Genotype; D005914:Globins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D011995:Recombination, Genetic; D013234:Stem Cells; D017085:alpha-Thalassemia / Q000097:blood / Q000196:embryology / Q000235:genetics*
D005914:Globins