Impaired Cx43 gap junction endocytosis causes morphological and functional defects in zebrafish

Area of Science:

• Cell Biology
• Molecular Biology
• Developmental Biology

Background:

• Gap junctions facilitate direct cell-to-cell communication via connexin (Cx) proteins.
• Connexin 43 (Cx43) is the most common Cx protein, but its rapid turnover (1-5 h half-life) is poorly understood.
• The Cx43 C-terminal (CT) domain regulates Cx43 function and gap junction turnover.

Purpose of the Study:

• To investigate the role of Cx43 CT domain in regulating gap junction endocytosis.
• To determine the physiological consequences of impaired Cx43 gap junction endocytosis.

Main Methods:

• Utilized cultured cells (Cx43^∆256-289) with a deleted Cx43 CT domain (amino acids 256-289).
• Employed a zebrafish model (cx43) to study the in vivo effects of altered Cx43.
• Assessed gap junction endocytosis, intercellular communication, Cx43 protein levels, plaque size, and developmental outcomes.

Main Results:

• Cx43 CT deletion resulted in defective gap junction endocytosis and increased intercellular communication.
• Zebrafish with impaired Cx43 showed increased Cx43 protein content, larger gap junction plaques, and prolonged Cx43 half-lives, particularly in cardiac tissue.
• These molecular changes correlated with severely impaired embryonic development and cardiovascular function.

Conclusions:

• Continuous endocytosis of Cx43 gap junctions is essential for normal gap junction function.
• Dysregulation of Cx43 endocytosis leads to significant physiological problems, impacting cardiovascular development and function.
• Targeting Cx43 endocytosis may offer therapeutic avenues for related developmental disorders.