ENU mutagenesis as a tool for understanding lung development and disease

Area of Science:

• Genetics and Developmental Biology
• Chemical Mutagenesis
• Mammalian Models

Background:

• N-ethyl-N-nitrosourea (ENU) is a chemical mutagen widely used for generating mouse mutants.
• ENU induces random point mutations, facilitating both gene-driven (reverse genetics) and phenotype-driven (forward genetics) research approaches.
• A high-efficiency ENU screen yields approximately 25 functional mutations per genome, predominantly hypomorphic alleles.

Purpose of the Study:

• To investigate the role of ENU mutagenesis in understanding lung development and disease pathogenesis.
• To identify novel recessive mutations affecting mouse lung development through a forward genetics screen.
• To explore gene-driven approaches for studying asthma using ENU-induced mutations in susceptibility genes.

Main Methods:

• Utilizing N-ethyl-N-nitrosourea (ENU) for chemical mutagenesis in mice.
• Conducting a forward genetics screen for recessive mutations impacting mouse lung development.
• Employing a gene-driven (reverse genetics) approach using the ENU sperm archive to study asthma-susceptibility genes.

Main Results:

• Two mutant mouse lines, Hel and RecBA17, exhibiting lung defects were identified from the forward genetics screen.
• Mutations in the asthma-susceptibility genes Phf11 and Dpp10 were recovered using the ENU sperm archive.
• Ongoing functional analyses aim to elucidate the impact of these identified mutations.

Conclusions:

• ENU mutagenesis is a powerful tool for dissecting the genetic basis of lung development and disease.
• Studying ENU-induced lung and asthma models can provide insights into human disease pathogenesis.
• Further characterization of identified alleles will advance our understanding of lung biology and asthma.