Autophagy is essential for cardiac morphogenesis during vertebrate development.
Genetic analyses indicate that autophagy, an evolutionarily conserved lysosomal degradation pathway, is essential for eukaryotic differentiation and development. However, little is known about whether autophagy contributes to morphogenesis during embryogenesis. To address this question, we examined the role of autophagy in the early development of zebrafish, a model organism for studying vertebrate tissue and organ morphogenesis. Using zebrafish that transgenically express the fluorescent autophagy reporter protein, GFP-LC3, we found that autophagy is active in multiple tissues, including the heart, during the embryonic period. Inhibition of autophagy by morpholino knockdown of essential autophagy genes (including atg5, atg7, and becn1) resulted in defects in morphogenesis, increased numbers of dead cells, abnormal heart structure, and reduced organismal survival. Further analyses of cardiac development in autophagy-deficient zebrafish revealed defects in cardiac looping, abnormal chamber morphology, aberrant valve development, and ectopic expression of critical transcription factors including foxn4, tbx5, and tbx2. Consistent with these results, Atg5-deficient mice displayed abnormal Tbx2 expression and defects in valve development and chamber septation. Thus, autophagy plays an essential, conserved role in cardiac morphogenesis during vertebrate development.
Department of Internal Medicine; University of Texas Southwestern Medical Center; Dallas, TX USA.
Eunmyong
E
Lee
Department of Molecular Biology; University of Texas Southwestern Medical Center; Dallas, TX USA.
Yeon
Y
Koo
Center for Computational & Integrative Biology; Massachusetts General Hospital; Boston, MA USA; Gastrointestinal Unit; Massachusetts General Hospital; Boston, MA USA; Broad Institute of Harvard and MIT; Cambridge, MA USA.
Aylwin
A
Ng
Department of Internal Medicine; University of Texas Southwestern Medical Center; Dallas, TX USA; Center for Autophagy Research; University of Texas Southwestern Medical Center; Dallas, TX USA; Howard Hughes Medical Institute; University of Texas Southwestern Medical Center; Dallas, TX USA.
Yongjie
Y
Wei
Department of Cell Biology; UT Southwestern Medical Center; Dallas, TX USA.
Kate
K
Luby-Phelps
Department of Pediatrics; University of Texas Southwestern Medical Center; Dallas, TX USA.
Amy
A
Juraszek
Center for Computational & Integrative Biology; Massachusetts General Hospital; Boston, MA USA; Gastrointestinal Unit; Massachusetts General Hospital; Boston, MA USA; Broad Institute of Harvard and MIT; Cambridge, MA USA.
Ramnik J
RJ
Xavier
Department of Molecular Biology; University of Texas Southwestern Medical Center; Dallas, TX USA.
Ondine
O
Cleaver
Department of Internal Medicine; University of Texas Southwestern Medical Center; Dallas, TX USA; Center for Autophagy Research; University of Texas Southwestern Medical Center; Dallas, TX USA; Howard Hughes Medical Institute; University of Texas Southwestern Medical Center; Dallas, TX USA; Department of Microbiology; University of Texas Southwestern Medical Center; Dallas, TX USA.
Beth
B
Levine
Department of Internal Medicine; University of Texas Southwestern Medical Center; Dallas, TX USA; Department of Molecular Biology; University of Texas Southwestern Medical Center; Dallas, TX USA; Department of Pediatrics; University of Texas Southwestern Medical Center; Dallas, TX USA.
James F
JF
Amatruda
D000818:Animals; D001343:Autophagy / Q000235:genetics*; D000071187:Autophagy-Related Protein 5; D002454:Cell Differentiation / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D006321:Heart / Q000254:growth & development*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009024:Morphogenesis / Q000235:genetics*; D015027:Zebrafish / Q000196:embryology; D029961:Zebrafish Proteins / Q000378:metabolism
C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D008869:Microtubule-Associated Proteins; D029961:Zebrafish Proteins
atg5; atg7; autophagy; becn1; heart development; tbx2; zebrafish