NORADRENALINE IS ESSENTIAL FOR MOUSE FETAL DEVELOPMENT

CATECHOLAMINES such as noradrenaline and adrenaline have been implicated in numerous physiological processes(1-4) but, although catecholamine synthesis begins at mid-gestation(5), previous studies have provided little evidence for any role in early development(6,7). Furthermore, there are several case reports of humans with noradrenaline deficiency(8). To investigate this, we used gene targeting(9) to produce mice lacking dopamine beta-hydroxylase and therefore unable to synthesize noradrenaline or adrenaline. We report here that in heterozygous mothers, most homozygous embryos died in utero, and only about 5% reached adulthood. Survival probably depends on catecholamine transfer across the placenta because, in homozygous mothers, all embryos die in utero. Mortality was due to lack of noradrenaline in utero because it could be prevented by treatment with dihydroxyphenylserine, a precursor that can be converted to noradrenaline in the absence of dopamine beta-hydroxylase. Mutant embryos had a histological phenotype similar to that of embryos deficient in tyrosine hydroxylase(10), suggesting that death might be due to cardiovascular failure.