Targeted disruption of the tyrosine hydroxylase gene reveals that catecholamines are required for mouse fetal development

Abstract

Tyrosine hydroxylase catalyses the initial, rate-limiting step in the catecholamine biosynthetic pathway. Catecholamines, which include dopamine, noradrenaline, and adrenaline, are important neurotransmitters and hormones that regulate visceral functions, motor coordination and arousal in adults. The gene encoding tyrosine hydroxylase becomes transcriptionally active in developing neuroblasts during mid-gestation of rodent embryos, before the onset of neurotransmission. Here we show that inactivation of both tyrosine hydroxylase alleles results in mid-gestational lethality: about 90% of mutant embryos die between embryonic days 11.5 and 15.5, apparently of cardiovascular failure. Administration of L-DOPA (dihydroxyphenylalanine), the product of the tyrosine hydroxylase reaction, to pregnant females results in complete rescue of mutant mice in utero. Without further treatment, however, they die before weaning. We conclude that catecholamines are essential for mouse fetal development and postnatal survival.