Abstract：
Mutations in the transcription factor Phox2b cause congenital central hypoventilation syndrome (CCHS). The syndrome is characterized by hypoventilation and inability to regulate breathing to maintain adequate O2 and CO2 levels. The mechanism by which CCHS impact respiratory control is incompletely understood, and even less is known about the impact of the non-polyalanine repeat expansion mutations (NPARM) form. Our goal was to investigate the extent by which NPARM Phox2b mutation affect (a) respiratory rhythm; (b) ventilatory responses to hypercapnia (HCVR) and hypoxia (HVR); and (c) number of chemosensitive neurons in mice. We used a transgenic mouse line carrying a conditional Phox2bΔ8 mutation (same found in humans with NPARM CCHS). We crossed them with Atoh1cre mice to introduce mutation in regions involved with respiratory function and central chemoreflex control. Ventilation was measured by plethysmograph during neonatal and adult life. In room air, mutation in neonates and adult did not greatly impact basal ventilation. However, Phox2bΔ8, Atoh1cre increased breath irregularity in adults. The HVR and HCVR were impaired in neonates. The HVR, but not HCVR, was still partially compromised in adults. The mutation reduced the number of Phox2b+/TH--expressing neurons as well as the number of fos-activated cells within the ventral parafacial region (also named retrotrapezoid nucleus [RTN] region) induced by hypercapnia. Our data indicates that Phox2bΔ8 mutation in Atoh1-expressing cells impaired RTN neurons, as well as chemoreflex under hypoxia and hypercapnia specially early in life. This study provided new evidence for mechanisms related to NPARM form of CCHS neuropathology.
摘要：
转录因子Phox2b的突变导致先天性中枢通气不足综合征(CCHS)。该综合征的特征是通气不足和无法调节呼吸以维持充足的O2和CO2水平。CCHS影响呼吸控制的机制尚未完全了解，甚至更少知道非聚丙氨酸重复扩增突变（NPARM）形式的影响。我们的目标是研究NPRMPhox2b突变影响（a）呼吸节律的程度；（b）对高碳酸血症（HCVR）和缺氧（HVR）的通气反应；（c）小鼠中化学敏感神经元的数量。我们使用了携带有条件的Phox2bΔ8突变的转基因小鼠系（在具有NPARMCCHS的人类中发现的相同）。我们将它们与Atoh1cre小鼠杂交，以在与呼吸功能和中枢化学反射控制有关的区域引入突变。在新生儿和成年期间通过体积描记器测量通气。在房间的空气中，新生儿和成人的突变对基础通气没有很大影响.然而,Phox2bΔ8，Atoh1cre增加了成年人的呼吸不规则性。新生儿HVR和HCVR受损。HVR,但不是HCVR，在成年人中仍然部分受损。该突变减少了高碳酸血症引起的腹侧面旁区域（也称为后梯形核[RTN]区域）内表达Phox2b/TH的神经元的数量以及fos激活细胞的数量。我们的数据表明，在Atoh1表达细胞中的Phox2bΔ8突变损害了RTN神经元，以及缺氧和高碳酸血症下的化学反射，特别是在生命早期。这项研究为CCHS神经病理学的NPARM形式相关机制提供了新的证据。
