Dissecting the Contribution of Specific Hindbrain Cell Populations in the Phenotypic Characterization of a Mouse Model of Central Congenital Hypoventilation Syndrome

Abstract

Hindbrain respiratory neuron networks undergo critical developmental maturation during the late embryonic, perinatal and post‐natal periods in mammals. Thus, abnormalities in neuron network development may contribute to autonomic respiratory dysfunction. Central Congenital Hypoventilation Syndrome (CCHS) is a rare genetic disorder characterized by an inability to sense and respond to altered levels of CO2 or O2 (Chemosensation). CCHS patients present with a spectrum of central respiratory control pathophysiologies, ranging from deficiency in chemosensation, to most severe manifestations of neonatal apnea that requires life‐sustaining mechanical ventilation. Heterozygous Mutations of the transcription factor PHOX2B, classified as either poly‐alanine repeat (PARM) and non‐poly‐alanine repeat (NPARM), have been linked to the development of CCHS. In order to explore CCHS pathophysiology, a novel transgenic mouse expressing an inducible NPARM Phox2b mutation (Phox2bΔ8) was developed and characterized by Nobuta and collaborators (Nabuta et al. 2015). Following this study and aiming to reveal the contribution of specific hindbrain populations to CCHS, we have generated two additional mouse models in which of Phox2bΔ8 expression is restricted to cell populations derived from either NKX2.2+ or OLIG3+ progenitors. Expression of Phox2bΔ8 on NKX2.2+ derived cells resulted in a strong apneic phenotype on newborn pups. Detail examination of this mouse model hindbrains showed deficiencies in a spectrum of rhombomeric nuclei not developmentally derived from NKX2.2+‐expressing progenitors, indicating that the developmental neuropathologies identified result through non‐cell‐autonomous mechanisms. Additionally, we find that these pathologies result from early rhombomeric patterning defects in embryonic ventral neural progenitor zones, which showed reduced endogenous PHOX2B expression. On the other hand, preliminary results indicate that expression of Phox2bΔ8 on OLIG3+ derived cells result in a subtle deficit in chemosensation, but we have been unable to find any neuropathological change in the hindbrain. Together, our results help to dissect the contributions of different cell populations in the hindbrain and to further clarify the different manifestations and severity of chemosensation and respiratory deficits seen in human CCHS patientsSupport or Funding InformationNIH R01HL132355This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.