NORADRENALINE IS ESSENTIAL FOR MOUSE FETAL DEVELOPMENT

CATECHOLAMINES such as noradrenaline and adrenaline have been implicat ed in numerous physiological processes(1-4) but, although catecholamin e 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 la cking dopamine beta-hydroxylase and therefore unable to synthesize nor adrenaline or adrenaline. We report here that in heterozygous mothers, most homozygous embryos died in utero, and only about 5% reached adul thood. Survival probably depends on catecholamine transfer across the placenta because, in homozygous mothers, all embryos die in utero. Mor tality was due to lack of noradrenaline in utero because it could be p revented by treatment with dihydroxyphenylserine, a precursor that can be converted to noradrenaline in the absence of dopamine beta-hydroxy lase. Mutant embryos had a histological phenotype similar to that of e mbryos deficient in tyrosine hydroxylase(10), suggesting that death mi ght be due to cardiovascular failure.