Distal-less 3 haploinsufficiency results in elevated placental oxidative stress and altered fetal growth kinetics in the mouse

Distal-less 3 (Dlx3)−/− mice die at E9.5 presumably due to an abnormal placental phenotype including reduced placental vasculature and secretion of placental growth factor. To examine the role of Dlx3 specifically within the epiblast, Dlx3 conditional knockout mice were generated using an epiblast-specific Meox2CreSor allele. Dlx3−/fl, Meox2CreSor animals were born at expected frequencies and survived to weaning providing indirect evidence that loss of Dlx3 within the trophoectoderm plays a critical role in fetal survival in the Dlx3−/− mouse. We next examined the hypothesis that loss of a single Dlx3 allele would have a negative impact on placental and fetal fitness. Dlx3+/− mice displayed reduced fetal growth beginning at E12.5 compared with Dlx3+/+ controls. Altered fetal growth trajectory occurred coincident with elevated oxidative stress and apoptosis within Dlx3+/− placentas. Oral supplementation with the superoxide dismutase mimetic, Tempol, rescued the fetal growth and placental cell death phenotypes in Dlx3+/− mice. To determine the potential mechanisms associated with elevated oxidative stress on the Dlx3+/− placentas, we next examined vascular characteristics within the feto-placental unit. Studies revealed reduced maternal spiral artery luminal area in the Dlx3+/− mice receiving water; Dlx3+/− mice receiving Tempol displayed maternal spiral artery luminal area similar to control Dlx3+/+ mice. We conclude that reduced Dlx3 gene dose results in diminished fetal fitness associated with elevated placental cell oxidative stress and apoptosis coincident with altered vascular remodeling. Administration of antioxidant therapy ameliorated this feto-placental phenotype, suggesting that Dlx3 may be required for adaptation to oxidative stresses within the intrauterine environment.