Neonatal apneic phenotype in a murine congenital central hypoventilation syndrome model is induced through non‐cell autonomous developmental mechanisms

Abstract

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.

Elevated Expression of MiR-17 in Microglia of Alzheimer’s Disease Patients Abrogates Autophagy-Mediated Amyloid-β Degradation

“…Immunofluorescence (IF) staining of mouse brain sections was performed as previously described ( 31 ). Slides were washed 3 times for 15min with PBS to remove residual OCT.…”

Research Advances on Therapeutic Approaches to Congenital Central Hypoventilation Syndrome (CCHS)

“…Recently, it has been shown that mutant Phox2b may induce secondary/non-cell autonomous defects of key brainstem respiratory neurons (Alzate-Correa et al, 2020). Indeed, the expression of NPARM PHOX2B mutation in Phox2b + nonrespiratory progenitor cells such as visceral motor neuron progenitors, induced a severe neonatal apnea along with a significant loss of neurons directly deriving from that specific progenitor domain but also from respiratory neural structures, such as RTN and preBötC, embriologically unrelated to that progenitor domain.…”

Obstructive Apneas in a Mouse Model of Congenital Central Hypoventilation Syndrome

“…Our finding of a dysgenesis of the hypoglossal nucleus thus showed that the Phox2b 27Ala /+ mutation elicits non-cell-autonomous mechanisms affecting respiratory networks. To date, such mechanisms were only reported in newborn mice with a non-polyalanine repeat mutation (the frameshift Phox2BΔ8 mutation), which expressed a dysfunctional preBötzinger complex, a non- Phox2b dependent brainstem site that is responsible for respiratory rhythmogenesis (33). Taken together, therefore, these findings widen the range of possible respiratory control disorders caused by Phox2b mutations.…”