Phox2b mutation mediated by Atoh1 expression impaired respiratory rhythm and ventilatory responses to hypoxia and hypercapnia.
Phox2b mutation mediated by Atoh1 expression impaired respiratory rhythm and ventilatory responses to hypoxia and hypercapnia.
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DOI：
10.7554/elife.73130
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发表时间：
2022-11-17
期刊：
影响因子：
7.7
通讯作者：
Moreira TS
中科院分区：
文献类型：
--
作者：
Ferreira CB;Silva TM;Silva PE;Castro CL;Czeisler C;Otero JJ;Takakura AC;Moreira TS
转录因子Phox2b的突变会导致先天性中枢性低通气综合征（CCHS）。该综合征的特征是通气不足以及无法调节呼吸以维持足够的氧气和二氧化碳水平。CCHS影响呼吸控制的机制尚未完全了解，对于非多聚丙氨酸重复扩增突变（NPARM）形式的影响所知更少。我们的目标是研究NPARM Phox2b突变在多大程度上影响（a）呼吸节律；（b）对高碳酸血症（HCVR）和低氧（HVR）的通气反应；以及（c）小鼠中化学敏感神经元的数量。我们使用了一种携带条件性Phox2bΔ8突变（在患有NPARM CCHS的人类中发现的相同突变）的转基因小鼠品系。我们将它们与Atoh1cre小鼠杂交，以便在涉及呼吸功能和中枢化学反射控制的区域引入突变。在新生期和成年期通过体积描记法测量通气量。在室内空气中，新生小鼠和成年小鼠的突变对基础通气量没有很大影响。然而，Phox2bΔ8、Atoh1cre增加了成年小鼠呼吸的不规则性。新生小鼠的HVR和HCVR受损。成年小鼠的HVR（但不是HCVR）仍然部分受损。该突变减少了表达Phox2b + /TH - 的神经元数量以及高碳酸血症诱导的腹侧面神经旁区域（也称为斜方体后核[RTN]区域）内fos激活细胞的数量。我们的数据表明，在表达Atoh1的细胞中Phox2bΔ8突变损害了RTN神经元，以及在低氧和高碳酸血症下的化学反射，特别是在生命早期。这项研究为与CCHS神经病理学的NPARM形式相关的机制提供了新的证据。
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.