Congenital central hypoventilation syndrome (CCHS) represents a rare genetic disorder usually caused by mutations in the homeodomain transcription factor PHOX2B. Some CCHS patients suffer mainly from deficiencies in CO₂ and/or O₂ respiratory chemoreflex, whereas other patients present with full apnea shortly after birth. Our goal was to identify the neuropathological mechanisms of apneic presentations in CCHS. In the developing murine neuroepithelium, Phox2b is expressed in three discrete progenitor domains across the dorsal‐ventral axis, with different domains responsible for producing unique autonomic or visceral motor neurons. Restricting the expression of mutant Phox2b to the ventral visceral motor neuron domain induces marked newborn apnea together with a significant loss of visceral motor neurons, RTN ablation, and preBötzinger complex dysfunction. This finding suggests that the observed apnea develops through non‐cell autonomous developmental mechanisms. Mutant Phox2b expression in dorsal rhombencephalic neurons did not generate significant respiratory dysfunction, but did result in subtle metabolic thermoregulatory deficiencies. We confirm the expression of a novel murine Phox2b splice variant which shares exons 1 and 2 with the more widely studied Phox2b splice variant, but which differs in exon 3 where most CCHS mutations occur. We also show that mutant Phox2b expression in the visceral motor neuron progenitor domain increases cell proliferation at the expense of visceral motor neuron development. We propose that visceral motor neurons may function as organizers of brainstem respiratory neuron development, and that disruptions in their development result in secondary/non‐cell autonomous maldevelopment of key brainstem respiratory neurons.

中文翻译：

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小鼠先天性中枢性低通气综合征模型中的新生儿呼吸暂停表型是通过非细胞自主发育机制诱导的

先天性中枢性低通气综合征 (CCHS) 是一种罕见的遗传疾病，通常由同源域转录因子PHOX2B突变引起。一些 CCHS 患者主要患有 CO ₂和/或 O ₂呼吸化学反射不足，而其他患者在出生后不久就出现完全呼吸暂停。我们的目标是确定 CCHS 中呼吸暂停表现的神经病理学机制。在发育中的小鼠神经上皮中，Phox2b在背腹轴的三个离散祖域中表达，不同的域负责产生独特的自主神经或内脏运动神经元。限制突变体Phox2b的表达腹侧内脏运动神经元结构域会引起明显的新生儿呼吸暂停以及内脏运动神经元的显着丧失、RTN 消融和preBötzinger复合体功能障碍。这一发现表明，观察到的呼吸暂停是通过非细胞自主发育机制发展起来的。背侧菱脑神经元中的突变体Phox2b表达不会产生明显的呼吸功能障碍，但会导致细微的代谢体温调节缺陷。我们证实了一种新的鼠Phox2b剪接变体的表达，它与更广泛研究的Phox2b剪接变体共享外显子 1 和 2，但在大多数 CCHS 突变发生的外显子 3 中不同。我们还展示了突变体Phox2b内脏运动神经元祖结构域的表达增加了细胞增殖，但内脏运动神经元的发育却被破坏了。我们提出内脏运动神经元可能充当脑干呼吸神经元发育的组织者，并且其发育的中断导致关键脑干呼吸神经元的继发性/非细胞自主发育不良。