Viemari J C, Bévengut M, Burnet H, Coulon P, Pequignot J M, Tiveron M C, Hilaire G
Biology of Rhythms and Development, Groupe d'Etude des Réseaux Moteurs-Centre National de la Recherche Scientifique, 13009 Marseille, France.
J Neurosci. 2004 Jan 28;24(4):928-37. doi: 10.1523/JNEUROSCI.3065-03.2004.
Although respiration is vital to the survival of all mammals from the moment of birth, little is known about the genetic factors controlling the prenatal maturation of this physiological process. Here we investigated the role of the Phox2a gene that encodes for a homeodomain protein involved in the generation of noradrenergic A6 neurons in the maturation of the respiratory network. First, comparisons of the respiratory activity of fetuses delivered surgically from heterozygous Phox2a pregnant mice on gestational day 18 showed that the mutants had impaired in vivo ventilation, in vitro respiratory-like activity, and in vitro respiratory responses to central hypoxia and noradrenaline. Second, pharmacological studies on wild-type neonates showed that endogenous noradrenaline released from pontine A6 neurons potentiates rhythmic respiratory activity via alpha1 medullary adrenoceptors. Third, transynaptic tracing experiments in which rabies virus was injected into the diaphragm confirmed that A6 neurons were connected to the neonatal respiratory network. Fourth, blocking the alpha1 adrenoceptors in wild-type dams during late gestation with daily injections of the alpha1 adrenoceptor antagonist prazosin induced in vivo and in vitro neonatal respiratory deficits similar to those observed in Phox2a mutants. These results suggest that noradrenaline, A6 neurons, and the Phox2a gene, which is crucial for the generation of A6 neurons, are essential for development of normal respiratory rhythm in neonatal mice. Metabolic noradrenaline disorders occurring during gestation therefore may induce neonatal respiratory deficits, in agreement with the catecholamine anomalies reported in victims of sudden infant death syndrome.
尽管呼吸从出生起对所有哺乳动物的生存至关重要，但对于控制这一生理过程产前成熟的遗传因素却知之甚少。在此，我们研究了Phox2a基因在呼吸网络成熟过程中的作用，该基因编码一种参与去甲肾上腺素能A6神经元生成的同源结构域蛋白。首先，对妊娠第18天从杂合子Phox2a怀孕小鼠手术分娩的胎儿的呼吸活动进行比较，结果显示突变体在体内通气、体外类似呼吸的活动以及体外对中枢性低氧和去甲肾上腺素的呼吸反应方面均受损。其次，对野生型新生儿的药理学研究表明，脑桥A6神经元释放的内源性去甲肾上腺素通过α1髓质肾上腺素能受体增强节律性呼吸活动。第三，将狂犬病毒注入膈肌的跨突触追踪实验证实A6神经元与新生儿呼吸网络相连。第四，在妊娠后期每天给野生型母鼠注射α1肾上腺素能受体拮抗剂哌唑嗪以阻断其α1肾上腺素能受体，可诱导出与Phox2a突变体中观察到的类似的体内和体外新生儿呼吸缺陷。这些结果表明，去甲肾上腺素、A6神经元以及对A6神经元生成至关重要的Phox2a基因，对于新生小鼠正常呼吸节律的发育至关重要。因此，妊娠期间发生的代谢性去甲肾上腺素紊乱可能会导致新生儿呼吸缺陷，这与婴儿猝死综合征受害者中报道的儿茶酚胺异常情况一致。
