Cholinergic Signaling Modulates Intestinal Pathophysiology in a Drosophila Model of Cystic Fibrosis

Area of Science:

• Genetics
• Physiology
• Molecular Biology

Background:

• Cystic Fibrosis (CF) is a genetic disorder caused by CFTR mutations, leading to persistent gastrointestinal issues.
• Current CF therapies often fail to fully address gut pathologies, necessitating novel treatment strategies.

Purpose of the Study:

• To investigate the gut-specific consequences of Cystic Fibrosis Transmembrane conductance Regulator (CFTR) loss using a Drosophila melanogaster model.
• To identify molecular mechanisms underlying CF-related gut dysfunction and explore potential therapeutic targets.

Main Methods:

• Enterocyte-specific knockdown of Cftr in Drosophila to model CF gut pathologies.
• Single-nuclei RNA sequencing (snRNA-seq) to analyze transcriptional changes in the CF gut model.
• Functional assays to assess cholinergic signaling and rescue of CF phenotypes.

Main Results:

• Drosophila Cftr knockdown recapitulated CF gut pathologies: reduced motility, malabsorption, and lower energy stores.
• CFTR loss upregulated acetylcholine esterase (Ace), diminishing cholinergic signaling.
• Restoring cholinergic signaling via Ace knockdown rescued CF-associated gut phenotypes.
• Forkhead (Fkh) was identified as a regulator of Ace expression in CF guts.

Conclusions:

• The Drosophila gut is a valuable model for studying CF pathogenesis and identifying genetic modifiers.
• Ace and Fkh are identified as key genetic modifiers of CFTR loss-of-function phenotypes.
• Enhancing cholinergic signaling presents a promising therapeutic avenue for managing gastrointestinal manifestations of CF.