Amiel Jeanne, Dubreuil Véronique, Ramanantsoa Nélina, Fortin Gilles, Gallego Jorge, Brunet Jean-François, Goridis Christo
INSERM U781, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France.
Respir Physiol Neurobiol. 2009 Aug 31;168(1-2):125-32. doi: 10.1016/j.resp.2009.03.005. Epub 2009 Mar 21.
Phox2b is a master regulator of visceral reflex circuits. Its role in the control of respiration has been highlighted by the identification of heterozygous PHOX2B mutations as the cause of Central Congenital Hypoventilation Syndrome (CCHS), a rare disease defined by the lack of CO(2) responsiveness and of breathing automaticity in sleep. Phox2b(27Ala/+) mice that bear a frequent CCHS-causing mutation do not respond to hypercapnia and die in the first hour after birth from central apnoea. They are therefore a reliable animal model for CCHS. Neurons of the retrotrapezoïd nucleus/parafacial respiratory group (RTN/pFRG) were found severely depleted in these mice and no other neuronal loss could be identified. Physiological experiments show that RTN/pFRG neurons are crucial to driving proper breathing at birth and are necessary for central chemoreception and the generation of a normal respiratory rhythm. To date, the reason for the selective vulnerability of RTN/pFRG neurons to PHOX2B protein dysfunction remains unexplained.
Phox2b是内脏反射回路的主要调节因子。杂合性PHOX2B突变被鉴定为中枢性先天性低通气综合征（CCHS）的病因，这一罕见疾病的特征是缺乏二氧化碳反应性以及睡眠时呼吸自主性，从而凸显了Phox2b在呼吸控制中的作用。携带常见的导致CCHS突变的Phox2b(27Ala/+)小鼠对高碳酸血症无反应，出生后第一小时死于中枢性呼吸暂停。因此，它们是CCHS的可靠动物模型。在这些小鼠中发现，后菱形核/面神经旁呼吸组（RTN/pFRG）的神经元严重减少，未发现其他神经元丢失。生理学实验表明，RTN/pFRG神经元对于出生时驱动正常呼吸至关重要，对于中枢化学感受和正常呼吸节律的产生也是必需的。迄今为止，RTN/pFRG神经元对PHOX2B蛋白功能障碍选择性易损的原因仍未得到解释。
