Spns1-dependent endocardial lysosomal function drives valve morphogenesis through Notch1-signaling.

Area of Science:

• Developmental Biology
• Cell Biology
• Cardiovascular Research

Background:

• Autophagy-lysosomal degradation is essential for cellular homeostasis and development.
• Its precise role and cell specificity during cardiac morphogenesis are not fully understood.

Purpose of the Study:

• To investigate the cell-specific function of autophagy-lysosomal degradation in zebrafish heart development.
• To elucidate the molecular mechanisms underlying cardiac defects in mutants with impaired lysosomal function.

Main Methods:

• Utilized zebrafish models for in vivo visualization of autophagic vesicles.
• Generated and analyzed Spinster homolog 1 (spns1) mutants (nrs) to study lysosomal degradation.
• Performed single-nuclear transcriptome analysis to identify gene expression changes.

Main Results:

• Observed accumulation of lysosomal vesicles in specific cardiac regions and valves.
• spns1 mutant larvae exhibited cardiac defects, including impaired valve formation and abnormal endocardial organization.
• Identified endocardial-specific gene expression differences and alterations in Notch signaling pathways.

Conclusions:

• Lysosomal degradation plays a cell-autonomous role in cardiac valve formation.
• This process is intrinsically linked to Notch signaling in endocardial cells.
• Findings provide new insights into the molecular basis of congenital heart defects.