Abstract
Autophagy is a catabolic process responsible for the removal of waste and damaged cellular components by lysosomal degradation. It plays a key role in fundamental cell processes, including ER stress mitigation, control of cell metabolism, and cell differentiation and proliferation, all of which are essential for cartilage cell (chondrocyte) development and survival, and for the formation of cartilage. Correspondingly, autophagy dysregulation has been implicated in several skeletal disorders such as osteoarthritis and osteoporosis. To test the requirement for autophagy during skeletal development in zebrafish, we generated an atg13 CRISPR knockout zebrafish line. This line showed a complete loss of atg13 expression, and restricted autophagic activity in vivo. In the absence of autophagy, chondrocyte maturation was accelerated, with chondrocytes exhibiting signs of premature hypertrophy. Focussing on the jaw element, autophagy disruption affected joint articulation causing restricted mouth opening. This gross behavioural phenotype corresponded with a failure to thrive, and death in homozygote atg13 nulls within 17days. Taken together, our results are consistent with autophagy contributing to the timely regulation of chondrocyte maturation and for extracellular matrix formation.
Highlights
Macroautophagy is a catabolic process which enables the breakdown of cytosolic components—including misfolded protein aggregates, redundant organelles, and invading microorganisms—into their basic biomolecular constituents by the actions of lysosomal acid hydrolases
We have shown that loss of a key autophagy protein, Atg[13], affects cartilage formation, joint function, and is detrimental to zebrafish larval survival
These data demonstrate that expression of atg[13] is essential for zebrafish survival, and that Atg[13] may play both autophagic and non-autophagic roles in development. This is in line with data from a previous study that showed that loss of Atg[13] in zebrafish affects swim bladder inflation and causes larval lethality.[25]
Summary
Macroautophagy ( termed autophagy) is a catabolic process which enables the breakdown of cytosolic components—including misfolded protein aggregates, redundant organelles, and invading microorganisms—into their basic biomolecular constituents by the actions of lysosomal acid hydrolases This cellular recycling pathway is essential during differentiation, and contributes to cell and tissue homeostasis, where its primary function is to mobilize nutrients to sustain vital cellular functions during stress.[1] It involves the formation of an isolation membrane that sequesters cytoplasmic cargo, and this membrane structure seals to form a new organelle—the autophagosome—which is subsequently delivered to the lysosome for degradation. The disruption to joint function seen in this model indicates an important role for autophagy in supporting the regulation of chondrocyte development to ensure proper joint formation and highlights an important pathway through which autophagy dysregulation may contribute to OA development
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