TARGETED DISRUPTION OF THE TYROSINE-HYDROXYLASE LOCUS RESULTS IN SEVERE CATECHOLAMINE DEPLETION AND PERINATAL LETHALITY IN MICE

Tyrosine 3-hydroxylase (TH, EC 1.14.16.2) catalyzes the first and rate -limiting step of the catecholamine biosynthetic pathway in the nervou s and endocrine systems. The TH locus was disrupted in mouse embryonic stem cells by homologous recombination, Mice heterozygous for the TH mutation were apparently normal, In these mice, TH activity in the emb ryos and adult tissues was less than 50% of the wild-type values, but the catecholamine level was decreased only moderately in the developin g animals and was maintained normally at adulthood, suggesting the pre sence of a regulatory mechanism for ensuring the proper catecholamine level during animal development, In contrast, the homozygous mutant mi ce died at a late stage of embryonic development or shortly after birt h. Both TH mRNA and enzyme activity were lacking in the homozygous mut ants, which thus explained the severe depletion of catecholamines. The se changes, however, did not affect gross morphological development of the cells that normally express high catecholamine levels, Analysis o f electrocardiograms of surviving newborn mutants showed bradycardia, suggesting an alteration of cardiac functions in the homozygous mice t hat may lead to the lethality of this mutation. In addition, transfer of a human TH transgene into the homozygous mice corrected the mutant phenotype, showing recovery of TH activity by expression of the human enzyme, These results indicate that TH is essential for survival of th e animals during the late gestational development and after birth.