Adenoviral supply of active transforming growth factor-beta1 (TGF-beta1) did not prevent lethality in transforming growth factor-beta1-knockout embryos.
In TGF-beta1-knockout mice, TGF-beta1-null conceptuses die during embryonic development with a penetrance of lethality that depends on the mouse genetic background. Studies have suggested that transplacental passage of maternal TGF-beta1 could account for the rescue of some TGF-beta1-null embryos. Herein, we have used an adenovirus-based gene delivery system and a strain of mice where most TGF-beta1-null conceptuses die prior to parturition, to investigate whether an increase in maternal TGF-beta1 during pregnancy would rescue TGF-beta1-null embryos. A single intravenous injection of an adenovirus containing a modified version of TGF-beta1 cDNA (Ad-TGF-beta1S223/S225), coding for a biologically active form of the cytokine, induced a 20-fold increase in plasma TGF-beta1 (active and latent forms) levels for up to 3 months in adult mice. Similar levels of TGF-beta1 were detected in 13-day post coïtum (dpc) embryos from Ad-TGF-beta1-treated mothers, demonstrating an efficient maternal/fetal transfer of the cytokine. However, no increase in the frequencies of TGF-beta1-null neonates nor in day 11.5 dpc TGF-beta1-null conceptuses was observed despite elevated levels of TGF-beta1 delivered throughout gestation. In addition, we show that the high levels of TGF-beta1-titrated in the plasma from Ad-TGF-beta1S223/S225-treated mice were partly the consequence of a stimulation of an autocrine production by exogenous bioactive TGF-beta1. These results indicate that transplacental passage of TGF-beta1 was not effective in rescuing TGF-beta1-null conceptuses from embryonic lethality.
Chagraoui
H
H
INSERM U. 362, Institut Gustave-Roussy, PR1, 39, rue Camille-Desmoulins, 94805 Villejuif, France. hchagra@igr.fr
Giraudier
S
S
Vainchenker
W
W
Wendling
F
F
D000256:Adenoviridae; D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D017931:DNA Primers; D005260:Female; D005838:Genotype; D008431:Maternal-Fetal Exchange; D051379:Mice; D018345:Mice, Knockout; D011247:Pregnancy; D016212:Transforming Growth Factor beta / Q000235:genetics*
D017931:DNA Primers; D016212:Transforming Growth Factor beta