PDF(Pubmed)
Abstract：
PHOX2B is a transcription factor essential for the development of different classes of neurons in the central and peripheral nervous system. Heterozygous mutations in the PHOX2B coding region are responsible for the occurrence of Congenital Central Hypoventilation Syndrome (CCHS), a rare neurological disorder characterised by inadequate chemosensitivity and life-threatening sleep-related hypoventilation. Animal studies suggest that chemoreflex defects are caused in part by the improper development or function of PHOX2B expressing neurons in the retrotrapezoid nucleus (RTN), a central hub for CO2 chemosensitivity. Although the function of PHOX2B in rodents during development is well established, its role in the adult respiratory network remains unknown. In this study, we investigated whether reduction in PHOX2B expression in chemosensitive neuromedin-B (NMB) expressing neurons in the RTN altered respiratory function. Four weeks following local RTN injection of a lentiviral vector expressing the short hairpin RNA (shRNA) targeting Phox2b mRNA, a reduction of PHOX2B expression was observed in Nmb neurons compared to both naive rats and rats injected with the non-target shRNA. PHOX2B knockdown did not affect breathing in room air or under hypoxia, but ventilation was significantly impaired during hypercapnia. PHOX2B knockdown did not alter Nmb expression but it was associated with reduced expression of both Task2 and Gpr4, two CO2/pH sensors in the RTN. We conclude that PHOX2B in the adult brain has an important role in CO2 chemoreception and reduced PHOX2B expression in CCHS beyond the developmental period may contribute to the impaired central chemoreflex function.
摘要：
PHOX2B是中枢神经系统和周围神经系统中不同类型神经元发育所必需的转录因子。PHOX2B编码区的杂合突变是先天性中枢通气不足综合征（CCHS）的发生原因，一种罕见的神经系统疾病，其特征是化学敏感性不足和危及生命的睡眠相关通气不足。动物研究表明，化学反射缺陷部分是由后梯形核（RTN）中表达PHOX2B的神经元的不适当发育或功能引起的，CO2化学敏感性的中心中心。尽管PHOX2B在啮齿动物发育过程中的功能已经确立，它在成人呼吸网络中的作用仍然未知。在这项研究中,我们调查了RTN中表达化学敏感性神经介质蛋白B(NMB)的神经元中PHOX2B表达的减少是否改变了呼吸功能。在局部RTN注射表达短发夹RNA（shRNA）靶向Phox2bmRNA的慢病毒载体四周后，与幼稚大鼠和注射非靶shRNA的大鼠相比,在Nmb神经元中观察到PHOX2B表达降低.PHOX2B敲除不影响室内空气或缺氧下的呼吸，但在高碳酸血症期间通气明显受损。PHOX2B敲低不会改变Nmb表达，但与RTN中两个CO2/pH传感器Task2和Gpr4的表达降低有关。我们得出的结论是，成人大脑中的PHOX2B在CO2化学接受中具有重要作用，并且在发育期之后，CCHS中PHOX2B的表达减少可能导致中枢化学反射功能受损。
