The role of PHOX2B-derived astrocytes in chemosensory control of breathing and sleep homeostasis

Czeisler, C. M., Silva, T. M., Fair, S. R., Liu, J., Tupal, S., Kaya, B., Cowgill, A., Mahajan, S., Silva, P. E., Wang, Y., Blissett, A. R., Goksel, M., Borniger, J. C., Zhang, N., Fernandes-Junior, S. A., Catacutan, F., Alves, M. J., Nelson, R. J., Sundaresean, V., Rekling, J., Takakura, A. C., Moreira, T. S., Otero, J. J. (April 2019) The role of PHOX2B-derived astrocytes in chemosensory control of breathing and sleep homeostasis. J Physiol, 597 (8). pp. 2225-2251. ISSN 1469-7793

Abstract

KEY POINTS: The embryonic PHOX2B-progenitor domain generates neuronal and glial cells which together are involved in chemosensory control of breathing and sleep homeostasis. Ablating PHOX2B-derived astrocytes significantly contributes to secondary hypoxic respiratory depression as well as abnormalities in sleep homeostasis. PHOX2B-derived astrocyte ablation results in axonal pathologies in the retrotrapezoid nucleus. ABSTRACT: We identify in mice a population of approximately 800 retrotrapezoid nucleus (RTN) astrocytes derived from PHOX2B-positive, OLIG3-negative progenitor cells, that interact with PHOX2B-expressing RTN chemosensory neurons. PHOX2B-derived astrocyte ablation during early life results in adult-onset O2 chemoreflex deficiency. These animals also display changes in sleep homeostasis, including fragmented sleep and disturbances in delta power after sleep deprivation, all without observable changes in anxiety or social behaviours. Ultrastructural evaluation of the RTN demonstrates that PHOX2B-derived astrocyte ablation results in features characteristic of degenerative neuro-axonal dystrophy, including abnormally dilated axon terminals and increased amounts of synapses containing autophagic vacuoles/phagosomes. We conclude that PHOX2B-derived astrocytes are necessary for maintaining a functional O2 chemosensory reflex in the adult, modulate sleep homeostasis, and are key regulators of synaptic integrity in the RTN region, which is necessary for the chemosensory control of breathing. These data also highlight how defects in embryonic development may manifest as neurodegenerative pathology in an adult.

Item Type:	Paper
Subjects:	bioinformatics bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification organism description > animal behavior > REM sleep organism description > animal organs, tissues, organelles, cell types and functions > cell types and functions > cell types > astrocytes organs, tissues, organelles, cell types and functions > cell types and functions > cell types > astrocytes organs, tissues, organelles, cell types and functions > cell types and functions > cell types > astrocytes organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell differentiation organs, tissues, organelles, cell types and functions > cell types and functions > cell functions organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions organism description > animal > mammal organism description > animal > mammal > rodent > mouse organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neurons organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neurons organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neurons organs, tissues, organelles, cell types and functions bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types organism description > animal > mammal > rodent bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > transcription factor
CSHL Authors:	Borniger, Jeremy
Communities:	CSHL labs > Borniger lab
Depositing User:	Adrian Gomez
Date:	April 2019
Date Deposited:	03 Jan 2020 19:58
Last Modified:	01 Feb 2024 21:12
PMCID:	PMC6462490
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/38859

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