# A genetic model of congenital intestinal atresia implicates Mypt1 in epithelial organisation

## TL;DR

A medaka fish model with a mutation in Mypt1 shows intestinal atresia, offering insights into how this gene affects intestinal development.

## Contribution

A new vertebrate model for MYPT1-associated intestinal atresia is established using medaka fish.

## Key findings

- Mypt1 loss in medaka leads to intestinal atresia through actomyosin dysregulation.
- Blebbistatin treatment rescues the intestinal defect in Mypt1 mutants.
- The model connects MYPT1 variants to human intestinal atresia.

## Abstract

Congenital intestinal atresia (IA) is a birth defect characterised by the absence or closure of part of the intestine. Although genetic factors are implicated, mechanistic understanding has been hindered by the lack of suitable animal models. Here, we describe a medaka (Oryzias latipes) mutant, generated by N-ethyl-N-nitrosourea (ENU) mutagenesis, that develops IA during embryogenesis. Positional cloning identified a nonsense mutation in mypt1, encoding myosin phosphatase target subunit 1. Mutant embryos exhibited ectopic accumulation of F-actin and phosphorylated myosin regulatory light chain (Mrlc) in the intestinal epithelium, consistent with disrupted actomyosin regulation. These cytoskeletal abnormalities were accompanied by epithelial disorganisation, without notable alterations in cell proliferation, motility or apoptosis. Inhibition of myh11a, encoding smooth muscle (SM) myosin heavy chain, ameliorated the IA phenotype, whereas blebbistatin treatment completely rescued the defect, suggesting a non-contractile role prior to SM maturation. Together, these findings demonstrate that mypt1 loss disrupts intestinal morphogenesis through actomyosin dysregulation. Given the recent clinical identification of IA associated with MYPT1 variants, this medaka model offers a valuable platform to investigate the developmental and molecular basis of MYPT1-associated IA in humans.

Summary: Loss of mypt1 causes intestinal atresia in medaka through localised actomyosin dysregulation, establishing a new vertebrate model of MYPT1-associated disease.