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Dissecting the Contribution of Specific Hindbrain Cell Populations in the Phenotypic Characterization of a Mouse Model of Central Congenital Hypoventilation Syndrome
Author(s) -
AlzateCorrea Diego,
Liu Jillian,
Jones Mikayla,
Alves Michele Joana,
Silva Talita Melo,
Baer Lisa,
Stanford Kristin,
Czeisler Catherine,
Otero Jose
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.802.51
Subject(s) - congenital central hypoventilation syndrome , hindbrain , biology , phenotype , embryonic stem cell , mutation , hypoventilation , genetics , gene , neuroscience , respiratory system , anatomy
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 CO 2 or O 2 (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 ( Phox2b Δ8 ) 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 Phox2b Δ8 expression is restricted to cell populations derived from either NKX2.2 + or OLIG3 + progenitors. Expression of Phox2b Δ8 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 Phox2b Δ8 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 patients Support or Funding Information NIH R01HL132355 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .