A hypomorphic lsd1 allele results in heart development defects in mice

Area of Science:

• Epigenetics and Developmental Biology
• Molecular and Cellular Biology

Background:

• Lysine-specific demethylase 1 (LSD1) is a key epigenetic regulator involved in demethylating histone and non-histone proteins.
• LSD1's interaction with other proteins, particularly through its tower domain, is crucial, but its role in development is not fully understood.
• Previous studies highlight LSD1's essential function in mouse embryogenesis.

Purpose of the Study:

• To investigate the functional significance of LSD1's tower domain interactions in vivo.
• To elucidate the role of LSD1 in mammalian development, specifically focusing on potential cardiac functions.

Main Methods:

• Generation and analysis of a hypomorphic Lsd1 allele with mutations in the tower domain.
• Phenotypic characterization of homozygous mutant mice, including detailed cardiac assessments.
• Molecular analysis of protein phosphorylation, specifically E-cadherin, in mutant heart tissues.

Main Results:

• Homozygous mice with the hypomorphic Lsd1 allele exhibit perinatal lethality, primarily due to severe heart defects like ventricular septal defects.
• The mutated Lsd1 protein shows reduced interaction with known binding partners and decreased enzymatic activity.
• Mutant hearts display hyperphosphorylation of E-cadherin, indicating a disruption in cell adhesion pathways.

Conclusions:

• LSD1 plays a critical, previously unrecognized role in heart development.
• Mutations affecting LSD1's tower domain interactions lead to significant cardiac abnormalities and developmental failure.
• LSD1 may regulate heart development partly by controlling E-cadherin phosphorylation.