Lamin Mutations Cause Increased YAP Nuclear Entry in Muscle Stem Cells

Area of Science:

• Cell Biology
• Genetics
• Biochemistry

Background:

• Mutations in the LMNA gene cause LMNA-related congenital muscular dystrophy (L-CMD), characterized by myonucleus integrity defects.
• L-CMD mutations impair muscle stem cell modulation of the yes-associated protein (YAP), crucial for mechanotransduction and myogenesis.

Purpose of the Study:

• To investigate the intrinsic mechanisms by which lamins influence YAP subcellular distribution.
• To analyze YAP nuclear import and export balance under different conditions in L-CMD mutations.

Main Methods:

• Analysis of YAP subcellular distribution in wild-type (WT) and mutant cells (LMNA^DK32, nesprin-1^ΔKASH, LMNA^H222P).
• Investigation of YAP nuclear import and export dynamics at different cell densities.
• Inhibition of nuclear pore import to assess YAP nuclear accumulation.

Main Results:

• LMNA^DK32 mutations prevent YAP exclusion from the nucleus and inactivation of its transcriptional activity at high cell density, despite Hippo pathway activation.
• Inhibition of nuclear pore import abolishes YAP nuclear accumulation in confluent mutant cells, indicating persistent nuclear import.
• YAP deregulation is observed in nesprin-1^ΔKASH-related congenital myopathy but not in LMNA^H222P mutation.

Conclusions:

• L-CMD mutations increase YAP nuclear localization through enhanced nuclear import.
• YAP deregulation is implicated as a pathogenic factor in muscle dystrophies arising from nuclear envelope defects.