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Some CCHS patients suffer mainly from deficiencies in CO<jats:sub>2<\/jats:sub> and\/or O<jats:sub>2<\/jats:sub> 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, <jats:italic>Phox2b<\/jats:italic> is expressed in three discrete progenitor domains across the dorsal\u2010ventral axis, with different domains responsible for producing unique autonomic or visceral motor neurons. Restricting the expression of mutant <jats:italic>Phox2b<\/jats:italic> to the ventral visceral motor neuron domain induces marked newborn apnea together with a significant loss of visceral motor neurons, RTN ablation, and <jats:italic>preB\u00f6tzinger<\/jats:italic> complex dysfunction. This finding suggests that the observed apnea develops through non\u2010cell autonomous developmental mechanisms. Mutant <jats:italic>Phox2b<\/jats:italic> 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 <jats:italic>Phox2b<\/jats:italic> splice variant which shares exons 1 and 2 with the more widely studied <jats:italic>Phox2b<\/jats:italic> splice variant, but which differs in exon 3 where most CCHS mutations occur. We also show that mutant <jats:italic>Phox2b<\/jats:italic> 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\u2010cell autonomous maldevelopment of key brainstem respiratory neurons.<\/jats:p>","DOI":"10.1111\/bpa.12877","type":"journal-article","created":{"date-parts":[[2020,7,12]],"date-time":"2020-07-12T08:02:32Z","timestamp":1594540952000},"page":"84-102","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Neonatal apneic phenotype in a murine congenital central hypoventilation syndrome model is induced through non\u2010cell autonomous developmental mechanisms"],"prefix":"10.1111","volume":"31","author":[{"given":"Diego","family":"Alzate\u2010Correa","sequence":"first","affiliation":[{"name":"Division of Neuropathology Department of Pathology The Ohio State University College of Medicine Columbus OH 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