期刊
BRAIN PATHOLOGY
卷 31, 期 1, 页码 84-102出版社
WILEY
DOI: 10.1111/bpa.12877
关键词
apnea; chemosensation; congenital central hypoventilation syndrome (CCHS); Nkx2; 2; PHOX2B; respiratory rhythm-generating networks
资金
- National Institute of Health/National Heart, Lung, and Blood Institute [NIH/NHLBI R01HL132355, R01HL138738]
- American Heart Association (AHA) [17CSA33610078]
- Sao Paulo Research Foundation (FAPESP) [2016/23281-3, 2015/23376-1, 2017/12678-2]
- FAPESP [2017/12678-2]
- NIH/NHLBI [PO1HL 144454]
- National Institute of Health/ The National Institute of Neurological Disorders and Stroke [NIH/NINDS R01 NS10742101]
- National Institute of Health/National Institute on Drug Abuse [NIH/NIDA T32DA043469]
The mutated Phox2b protein expression in neurons is associated with apneic episodes in CCHS patients shortly after birth, possibly due to disruptions in visceral motor neuron development.
Congenital central hypoventilation syndrome (CCHS) represents a rare genetic disorder usually caused by mutations in the homeodomain transcription factorPHOX2B. Some CCHS patients suffer mainly from deficiencies in CO(2)and/or O(2)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,Phox2bis 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 mutantPhox2bto the ventral visceral motor neuron domain induces marked newborn apnea together with a significant loss of visceral motor neurons, RTN ablation, andpreBotzingercomplex dysfunction. This finding suggests that the observed apnea develops through non-cell autonomous developmental mechanisms. MutantPhox2bexpression 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 murinePhox2bsplice variant which shares exons 1 and 2 with the more widely studiedPhox2bsplice variant, but which differs in exon 3 where most CCHS mutations occur. We also show that mutantPhox2bexpression 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.
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