Rnx deficiency results in congenital central hypoventilation
Rnx deficiency results in congenital central hypoventilation
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Rnx 缺乏导致先天性中枢性通气不足
作者：
S. Shirasawa;A. Arata;H. Onimaru;K. Roth;Gary A. J. Brown;Susan E. Horning;S. Arata;Koji Okumura;T. Sasazuki;S. Korsmeyer
基因 Tlx1 (Hox11)、Enx (Hox11L1、Tlx-2) 和 Rnx (Hox11L2、Tlx-3) 构成孤儿同源框基因家族。原位杂交揭示了它们在神经系统内的表达有相当大的重叠，但 Rnx 仅在延髓发育中的背侧和腹侧区域表达。 Tlx1缺陷型和Enx缺陷型小鼠在突变基因单一表达的组织中表现出表型，分别导致脾生成和超神经节巨结肠。为了确定 Rnx 的发育作用，我们破坏了小鼠胚胎干 (ES) 细胞中的基因座。 Rnx 缺陷小鼠发育至足月，但全部在出生后 24 小时内死于中枢性呼吸衰竭。肋间肌的肌电活动与髓质-脊髓制剂中评估的 C4 腹侧根活动相结合，显示呼吸频率高，吸气持续时间短，呼吸暂停频繁。此外，腹外侧延髓吸气神经元的异常活动与 C4 运动神经元输出之间存在协调模式，表明 Rnx−/− 小鼠存在中枢呼吸缺陷。因此，Rnx 对于腹侧延髓呼吸中枢的发育至关重要，其缺乏会导致类似于先天性中枢通气不足的综合征。
The genes Tlx1 (Hox11), Enx (Hox11L1, Tlx-2 ) and Rnx (Hox11L2, Tlx-3) constitute a family of orphan homeobox genes. In situ hybridization has revealed considerable overlap in their expression within the nervous system, but Rnx is singularly expressed in the developing dorsal and ventral region of the medulla oblongata. Tlx1-deficient and Enx-deficient mice display phenotypes in tissues where the mutated gene is singularly expressed, resulting in asplenogenesis and hyperganglionic megacolon, respectively. To determine the developmental role of Rnx, we disrupted the locus in mouse embryonic stem (ES) cells. Rnx-deficient mice developed to term, but all died within 24 hours after birth from a central respiratory failure. The electromyographic activity of intercostal muscles coupled with the C4 ventral root activity assessed in a medulla-spinal cord preparation revealed a high respiratory rate with short inspiratory duration and frequent apnea. Furthermore, a coordinate pattern existed between the abnormal activity of inspiratory neurons in the ventrolateral medulla and C4 motorneuron output, indicating a central respiratory defect in Rnx−/− mice. Thus, Rnx is critical for the development of the ventral medullary respiratory centre and its deficiency results in a syndrome resembling congenital central hypoventilation.