Cytoglobin regulates NO-dependent cilia motility and organ laterality during development

Elizabeth R Rochon1, Jianmin Xue2, Manush Sayd Mohammed3

  • 1Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.

Nature Communications
|December 14, 2023
PubMed

Insights

Cytoglobin is essential for proper cilia function and organ development. This heme protein regulates a nitric oxide signaling pathway crucial for left-right patterning in zebrafish and airway cilia in mice.

Area of Science:

  • Biochemistry
  • Developmental Biology
  • Cell Biology

Background:

  • Cytoglobin (CYGB) is a heme protein with an unclear physiological role.
  • Human conditions linked to ciliary dysfunction and low nitric oxide (NO) production involve left-right cardiac determination defects.
  • Zebrafish cytoglobin (cygb2) genetic deletion results in cardiac developmental abnormalities.

Purpose of the Study:

  • To investigate the physiological function of cytoglobin, specifically its role in cilia function and organ laterality.
  • To elucidate the molecular mechanisms underlying cytoglobin's function in relation to nitric oxide signaling.

Main Methods:

  • Utilized zebrafish (cygb2) mutants and cytoglobin knockout mice models.
  • Investigated co-localization of Cygb2 with cilia and nitric oxide synthase (Nos2b).
  • Assessed cilia structure and function, organ laterality, and nitric oxide levels.

Main Results:

  • Cygb2 was found to co-localize with cilia and Nos2b in zebrafish Kupffer's vesicle, with disrupted cilia structure and function in cygb2 mutants.
  • Depletion of Nos2b or guanylate cyclase (gucy1a) phenocopied the ciliary and laterality defects.
  • Defects were rescued by NO donors, guanylate cyclase stimulators, or Nos2b overexpression in zebrafish.
  • Cytoglobin knockout mice exhibited impaired airway cilia structure and reduced NO levels.

Conclusions:

  • Cytoglobin acts as a positive regulator of the nitric oxide synthase-soluble guanylate cyclase-cyclic GMP signaling pathway.
  • This pathway is critical for normal cilia motility and left-right patterning.
  • Cytoglobin's role in NO signaling is conserved across species, impacting both embryonic development and airway function.

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