Expression of wild-type or PBX interaction defective PDX-1 transgenes
rescues glucose homeostasis in pdx-1
(+/−) mice. (A) Transient transfection
assay of wild-type and PBX interaction defective (Pdxμ) PDX-1
constructs in 293T cells, with a TSEII luciferase reporter containing
two PDX:PBX heterodimer recognition sites. Cells were transfected with
wild-type or mutant PDX plus E2A-PBX expression vector where indicated.
The first bar on the left represents control transfection with empty
vector alone plus TSEII reporter. Luciferase activity shown after
normalizing to β-galactosidase activity from cotransfected RSV-βgal
plasmid. (B) Genotypic analysis of mice expressing PDX-1
transgene. (Left) Inheritance of PDX-1 transgene was
evaluated by PCR assay with primers that are selective for rat PDX-1.
(Right) Mice heterozygous or homozygous for targeted
disruption of the murine PDX-1 gene were identified by genomic Southern
blot analysis with a 32P-labeled PDX-1 cDNA probe.
Insertion of the inactivating β-galactosidase gene is indicated by a
3.8-kb vs. a 3.0-kb EcoRI fragment. (C)
Wild-type (Lane 1) and mutant (Lane 2) PDX-1 transgenes are comparably
expressed in transgenic mice. (Left) RNase protection
assay of total RNA from whole pancreas of adult mice, with the use of
32P-labeled wild-type PDX-1 antisense RNA probe. The
shorter fragment in mutant mice results from RNase digestion in
sequences encoding mutant FPWMK/AAGGQ motif. Lane 3, control
nontransgenic littermate RNA; the rat PDX-1 probe does not recognize
murine PDX-1. Lane 4, position of undigested PDX-1 antisense probe.
Lane 5, molecular weight marker. (Right) Western blot
assay of whole pancreas extract, showing levels of PDX-1 protein in
wild-type, pdx-1(+/−),
pdx-1(+/−);mTg, and
pdx-1(−/−);wtTg mice. (D) Line graph
of blood glucose levels in wild-type (—■—),
pdx-1(+/−) heterozygous (– –⧫– –),
pdx-1(+/−); wtTg, and pdx-1
(+/−);mTg mice
(⋅⋅⋅●⋅⋅⋅) after
i.p. glucose injection. Results for pdx-1(+/−); wtTg
and pdx-1(+/−);mTg mice were indistinguishable.