Deficiency of Werner RecQ-type DNA helicase causes premature malnutrition in zebrafish

TL;DR

Zebrafish lacking the WRN gene show early signs of malnutrition and organ defects, leading to premature death, which can be partially improved with more food.

Contribution

This study identifies early-onset malnutrition and organ defects in zebrafish WRN mutants, revealing new insights into Werner syndrome pathology.

Findings

Severe wrn mutants showed high DNA damage and apoptosis, causing gut and pancreatic defects.

Severe wrn mutants exhibited low glucose, glycogen, and fat levels, indicating malnutrition.

Increased food availability partially rescued the survival of wrn mutant zebrafish.

Abstract

Werner syndrome is a genetic progeria characterized by premature aging symptoms, but its early-onset pathology remains unclear. We generated wrn truncation mutant (wrn-/-) zebrafish using CRISPR/Cas9 and identified two premature mortality phases: 7–21 and 60–90 days post-fertilization (dpf). Time-course transcriptomics revealed two wrn-/- subgroups. One showed the reduced expression of intestinal and pancreatic exocrine genes at 7–9 dpf, while the other maintained normal expression initially but eventually showed reduced pancreatic exocrine genes by 21–35 dpf. The prematurely dying wrn-/- larvae exhibited intestinal villi and pancreatic defects, along with DNA damage, cell-cycle arrest, and apoptosis. They also had lower glycogen, glucose, and fat levels compared to wild-type and late-dying wrn-/- larvae, suggesting malnutrition. Notably, excess feeding partially improved their survival. These findings reveal early pathological features in the zebrafish model of Werner syndrome.

•Zebrafish wrn truncated mutants segregate into mild and severe phenotypic classes•Severe wrn mutants showed high DNA damage and apoptosis, causing gut and pancreatic defects•Severe wrn mutants showed low glucose, glycogen, and fat levels, indicating malnutrition•Increased food availability partially rescued the survival of wrn mutant zebrafish

Zebrafish wrn truncated mutants segregate into mild and severe phenotypic classes

Severe wrn mutants showed high DNA damage and apoptosis, causing gut and pancreatic defects

Severe wrn mutants showed low glucose, glycogen, and fat levels, indicating malnutrition

Increased food availability partially rescued the survival of wrn mutant zebrafish

Developmental biology; Pathophysiology

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