Autophagy is essential for cardiac morphogenesis during vertebrate development

Lee, Eunmyong; Koo, Yeon; Ng, Aylwin; Wei, Yongjie; Luby-Phelps, Katherine; Juraszek, Amy L.; Xavier, Ramnik J.; Cleaver, Ondine; Levine, Beth; Amatruda, James F.

doi:10.4161/auto.27649

Cited by 122 publications

(100 citation statements)

References 60 publications

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“…Autophagy occurs during cardiac development in zebrafish (Lee et al 2014). Zebrafish mutants with knockdown of Atg5, Atg7 and BECN1 genes by antisense morpholino oligonucleotides exhibit similar cardiac defects including pericardial edema, defect in blood flow through the heart, defective heart looping, enlarged atria, or linearized hearts, although the penetrance is distinct with 80% of BECN1 morphants, 62% of Atg5 morphants and 30% of Atg7 morphants.…”

Section: Atg5/atg7/becn1 Knockdown Zebrafishmentioning

confidence: 99%

“…In addition, knockdown of Atg genes leads to increased number of apoptotic cell death. Gene expression profiling shows that many genes involved in cardiac development and function, especially transcription factors including foxn4, tbx5, and tbx2, are aberrantly expressed (Lee et al 2014). Thus, autophagy regulates the transcription program and cardiac morphogenesis during cardiac development, though the precise mechanisms remain to be elucidated.…”

Section: Atg5/atg7/becn1 Knockdown Zebrafishmentioning

confidence: 99%

“…Cardiac defects observed in mice deficient for distinct Atg genes are not identical. For instance, the penetrance of cardiac defects is discrepant in Atg5, Atg7 or BECN1 knockdown zebrafish, with 100% of Atg5 mutants, over 80% of BECN1 mutants and approximately 30% of Atg7 mutants displaying cardiac defects (Lee et al 2014). Moreover, mice deficient for FIP200 and Atg13 show distinct cardiac defects from Atg5-deficient mice (Gan et al 2006, Kaizuka & Mizushima 2015, Lee et al 2014.…”

Section: Autophagy-independent Functionsmentioning

confidence: 99%

“…For instance, the penetrance of cardiac defects is discrepant in Atg5, Atg7 or BECN1 knockdown zebrafish, with 100% of Atg5 mutants, over 80% of BECN1 mutants and approximately 30% of Atg7 mutants displaying cardiac defects (Lee et al 2014). Moreover, mice deficient for FIP200 and Atg13 show distinct cardiac defects from Atg5-deficient mice (Gan et al 2006, Kaizuka & Mizushima 2015, Lee et al 2014. Considering that mammalian orthologues of almost all Atg genes identified so far have autophagyindependent activities, cardiac malformations observed in autophagydeficient mice may be ascribed to defects in autophagy-independent functions of these genes.…”

Section: Autophagy-independent Functionsmentioning

confidence: 99%

“…In contrast to cardiomyocyte-specific Atg5 knockout mice, conventional Atg5 knockout mice have enlarged atria and display cardiac defects including abnormal valve morphology, membranous ventricular septal defects and thickened valves. Transcription factors tbx2 is aberrantly expressed in the heart at E9.5 (Lee et al 2014). This study suggests that autophagy is also required in cardiac development in mammals.…”

Section: Atg5 Knockout Micementioning

confidence: 99%

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Autophagy in Cardiac Development

Zhu

2017

MRAJ

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The heart is the first functional organ to form during embryogenesis. Cardiac development is a multifactorial complex process requiring precise control of proliferation, differentiation, migration and survival of diverse cell types by interactive networks of genetic and environmental factors. Autophagy is a conserved catabolic pathway that degrades cytoplasmic contents in lysosomes for reutilization. It is well established that autophagy regulates the development of the nervous system, osseous tissue, adipose tissue and lymphocyte. Recent evidences on the basis of in vitro cell culture systems as well as in vivo animal models suggest essential roles of autophagy in cardiogenesis. In this review, we summarize the major findings regarding emerging roles of autophagy and autophagyrelated genes in cardiac development, which implicates autophagy in human congenital heart disease, the leading human birth defect worldwide.

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Section: Atg5/atg7/becn1 Knockdown Zebrafishmentioning

confidence: 99%

Section: Atg5/atg7/becn1 Knockdown Zebrafishmentioning

confidence: 99%

Section: Autophagy-independent Functionsmentioning

confidence: 99%

Section: Autophagy-independent Functionsmentioning

confidence: 99%

Section: Atg5 Knockout Micementioning

confidence: 99%

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Autophagy in Cardiac Development

Zhu

2017

MRAJ

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Extracellular pH regulates autophagy via the AMPK–ULK1 pathway in rat cardiomyocytes

et al. 2016

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Various pathological conditions contribute to pH fluctuations and affect the functions of vital organs such as the heart. In this study, we show that in rat cardiomyocytes, acidic extracellular pH (pHe) inhibits autophagy, whereas alkaline pHe stimulates it. We also find that adenosine monophosphate-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR) and Unc-51-like kinase 1 (ULK1) are very sensitive to pHe changes. Furthermore, by interfering with AMPK, mTOR or ULK1 activity, we demonstrate that the AMPK-ULK1 pathway, but not the mTOR pathway, plays a crucial role on pHe-regulated autophagy and cardiomyocyte viability. These data provide a potential therapeutic strategy against cardiomyocyte injury triggered by pH fluctuations.

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Beclin 1 deficiency causes hepatic cell apoptosis via endoplasmic reticulum stress in zebrafish larvae

et al. 2019

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Edited by Didier StainierBeclin 1/Atg6 is an essential autophagy gene, and deficiency of this gene in organisms leads to impaired autophagic flux, usually with cell apoptosis; however, the causative mechanism of cell apoptosis is not clear. Here, we knocked out the beclin 1 gene in zebrafish and found that autophagic flux is disrupted in mutants. Beclin 1-deficient zebrafish live through embryogenesis but die at larval stage. We found accumulated protein aggregates and vigorous apoptosis in mutant larvae, predominantly in the liver. The hepatic cell apoptosis in mutants results from an endoplasmic reticulum (ER) stress response; however, it is not the leading cause of mutant larval lethality. Our work proposes that ER stress induces cell apoptosis in Beclin 1-deficient organisms.Autophagy is an ancient self-digestive mechanism in eukaryotic cells, delivering cytoplasmic materials into the lysosome for degradation. The cargoes include damaged organelles, aberrant proteins, invading pathogens, and other cellular contents. The digestive products can be used for macromolecule synthesis and energy production. Therefore, autophagy plays important roles in the maintenance of cellular hemostasis, response to energy deprivation, and clearance of invading microorganism pathogen [1,2]. Among the three types of autophagy, namely microautophagy, chaperone-mediated autophagy, and macroautophagy, macroautophagy draws the most attention [3,4] and is hereafter called autophagy in this study. Autophagy is regulated by a group of genes, known as autophagy-related gene (Atg), with majority of them firstly identified by genetic screens in yeast and highly conserved among species [5]. Beclin 1/Atg6 is an essential for autophagy induction. It directly binds to Vps34 (Pik3c3) through its evolutionarily conserved domain (ECD) forming the class III phosphatidylinositol 3-kinase (PI3KIII) complex to produce phosphatidylinositol 3-phosphate (PtdIns(3)P), an essential lipid-based compound for initial steps of autophagosome formation [6].To study the biological functions of Beclin 1/Atg6, the loss-of-function mutants were generated in many Abbreviations Atg, autophagy-related gene; BH3, Bcl-2 homology-3 domain; CCD, coiled-coil domain; ECD, evolutionarily conserved domain; ER, endoplasmic reticulum; PC, Purkinje cell; PI3KIII, class III phosphatidylinositol 3-kinase; PtdIns(3)P, phosphatidylinositol 3-phosphate; TUDCA, tauroursodeoxycholic acid; VE, visceral endoderm; WISH, Whole-mount in situ hybridization.

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Autophagy is essential for cardiac morphogenesis during vertebrate development

Cited by 122 publications

References 60 publications

Autophagy in Cardiac Development

Autophagy in Cardiac Development

Extracellular pH regulates autophagy via the AMPK–ULK1 pathway in rat cardiomyocytes

Beclin 1 deficiency causes hepatic cell apoptosis via endoplasmic reticulum stress in zebrafish larvae

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