TARGETED DISRUPTION OF THE TYROSINE-HYDROXYLASE GENE REVEALS THAT CATECHOLAMINES ARE REQUIRED FOR MOUSE FETAL DEVELOPMENT
TARGETED DISRUPTION OF THE TYROSINE-HYDROXYLASE GENE REVEALS THAT CATECHOLAMINES ARE REQUIRED FOR MOUSE FETAL DEVELOPMENT
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DOI：
10.1038/374640a0
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发表时间：
1995-04-13
期刊：
影响因子：
64.8
通讯作者：
PALMITER, RD
中科院分区：
文献类型：
--
作者：
ZHOU, QY;QUAIFE, CJ;PALMITER, RD
酪氨酸羟化酶催化儿茶酚胺生物合成途径中的初始限速步骤。儿茶酚胺包括多巴胺、去甲肾上腺素和肾上腺素，是调节成人内脏功能、运动协调和唤醒的重要神经递质和激素(1)。在啮齿动物胚胎妊娠中期、神经传递开始之前，编码酪氨酸羟化酶的基因在发育中的神经母细胞中变得转录活跃(2-6)。在这里，我们表明，两个酪氨酸羟化酶等位基因的失活会导致妊娠中期致死：大约 90% 的突变胚胎在胚胎第 11.5 天至 15.5 天之间死亡，显然是死于心血管衰竭。将酪氨酸羟化酶反应的产物 L-DOPA（二羟基苯丙氨酸）给予怀孕雌性，可彻底拯救子宫内的突变小鼠。然而，如果不进行进一步治疗，它们就会在断奶前死亡。我们得出的结论是，儿茶酚胺对于小鼠胎儿发育和产后生存至关重要。
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(1). The gene encoding tyrosine hydroxylase becomes transcriptionally active in developing neuroblasts during mid-gestation of rodent embryos, before the onset of neurotransmission(2-6). 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.