Neonatal apneic phenotype in a murine congenital central hypoventilation syndrome model is induced through non‐cell autonomous developmental mechanisms
Diego Alzate‐Correa, Jillian Mei‐ling Liu, Mikayla Jones, Talita M. Silva, Michele Joana Alves, Elizabeth Burke, Jessica N. Zuniga, Behiye Kaya, Giuliana Zaza, Mehmet Aslan, Jessica Blackburn, Marina Y. Shimada, Silvio A. Fernandes‐Junior, Lisa A. Baer, Kristin I. Stanford, Amber Kempton, Sakima A. Smith, Caroline Szujewski, Abby Silbaugh, Jean‐Charles Viemari, Ana C. Takakura, Alfredo J. Garcia, Thiago S. Moreira, Catherine Czeisler, José Javier Otero
Abstract
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.