Spns1-dependent endocardial lysosomal function drives valve morphogenesis through Notch1-signaling
Myra N. Chávez,
Prateek Arora,
Marco Meer,
Ines J. Marques,
Alexander Ernst,
Rodrigo A. Morales Castro,
Nadia Mercader
Affiliations
Myra N. Chávez
Department of Developmental Biology and Regeneration, Institute of Anatomy, University of Bern, 3012 Bern, Switzerland; Corresponding author
Prateek Arora
Department of Developmental Biology and Regeneration, Institute of Anatomy, University of Bern, 3012 Bern, Switzerland; Department for Biomedical Research, University of Bern, 3008 Bern, Switzerland
Marco Meer
Department of Developmental Biology and Regeneration, Institute of Anatomy, University of Bern, 3012 Bern, Switzerland; Department for Biomedical Research, University of Bern, 3008 Bern, Switzerland
Ines J. Marques
Department of Developmental Biology and Regeneration, Institute of Anatomy, University of Bern, 3012 Bern, Switzerland; Department for Biomedical Research, University of Bern, 3008 Bern, Switzerland
Alexander Ernst
Department of Developmental Biology and Regeneration, Institute of Anatomy, University of Bern, 3012 Bern, Switzerland
Rodrigo A. Morales Castro
Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet and University Hospital, Stockholm, Sweden; Center of Molecular Medicine, Karolinska Institutet, 17176 Stockholm, Sweden
Nadia Mercader
Department of Developmental Biology and Regeneration, Institute of Anatomy, University of Bern, 3012 Bern, Switzerland; Department for Biomedical Research, University of Bern, 3008 Bern, Switzerland; Centro Nacional de Investigaciones Cardiovasculares Carlos III, 28029 Madrid, Spain; Corresponding author
Summary: Autophagy-lysosomal degradation is a conserved homeostatic process considered to be crucial for cardiac morphogenesis. However, both its cell specificity and functional role during heart development remain unclear. Here, we introduced zebrafish models to visualize autophagic vesicles in vivo and track their temporal and cellular localization in the larval heart. We observed a significant accumulation of autolysosomal and lysosomal vesicles in the atrioventricular and bulboventricular regions and their respective valves. We addressed the role of lysosomal degradation based on the Spinster homolog 1 (spns1) mutant (not really started, nrs). nrs larvae displayed morphological and functional cardiac defects, including abnormal endocardial organization, impaired valve formation and retrograde blood flow. Single-nuclear transcriptome analyses revealed endocardial-specific differences in lysosome-related genes and alterations of notch1-signalling. Endocardial-specific overexpression of spns1 and notch1 rescued features of valve formation and function. Altogether, our results reveal a cell-autonomous role of lysosomal processing during cardiac valve formation affecting notch1-signalling.
