Early embryonic development in oviparous animals relies on yolk substances stored in the yolk sac. These substances, including maternal RNA, proteins, and lipids formed during oocyte development, are utilized by the embryo during its development. While the roles of maternal RNA and proteins in early development are well understood, how maternal lipids are used and regulate embryogenesis remains unclear.

As oviparous models, fish depend entirely on yolk and their metabolites for embryonic development before exogenous feeding begins, making them ideal for studying the regulation of maternal lipids. In aquaculture, efficient yolk utilization and the transition from endogenous to exogenous nutrition (eeNST) are crucial for hatching, larval survival, and farming efficiency. Zebrafish, in particular, serve as a valuable model for investigating the mechanisms underlying eeNST.

A recent study, published in Nature Communications and led by Prof. SUN Yonghua from the Institute of Hydrobiology (IHB) of the Chinese Academy of Sciences, unveiled that the intestinal docosahexaenoic acid-phosphatidic acid-phosphatidylglycerol (DHA-PA-PG) axis promotes digestive organ expansion by mediating the use of maternally deposited yolk lipids.

In this study, researchers focused on the role of long-chain polyunsaturated fatty acids (LC-PUFAs) in yolk lipid absorption during embryonic development. They observed a significant increase in omega-3 PUFAs (n-3 PUFAs) before the transition from eeNST, indicating active lipid remodeling.

Using RNA sequencing, researchers identified the high expression of the LC-PUFA synthesis gene hsd17b12a in the primitive intestine. Through CRISPR/Cas9 and induced primordial germ cell (iPGC)-based gene knock-in technology, they created a hsd17b12a knock-in line, confirming its specific expression in intestinal epithelial cells.

After detecting the expression levels of genes related to the LC-PUFA synthesis pathway and the content of LC-PUFA, researchers found that a deficiency in hsd17b12a impaired LC-PUFA synthesis in the primitive intestine, which caused defective yolk absorption, failure of swim bladder inflation, and embryonic death, thus preventing the eeNST transition. They also observed the structural and functional abnormalities in the primitive intestine and the disrupted expansion of digestive organs such as the pancreas and liver.

Furthermore, single-cell RNA sequencing demonstrated the activation of the ferroptosis signaling pathway in the primitive intestine. The suppression of ferroptosis with Fer-1 rescued some of the defects. The lipidomics analysis identified a DHA-PA-PG metabolic axis in the primitive intestine, and the disruption of this axis caused ferroptosis and impaired the expansion of digestive organs.

This study reveals a novel mechanism by which the DHA-PA-PG axis in the primitive intestine regulates lipid utilization and organ expansion. It shows that the loss of hsd17b12a disrupts this axis, leading to developmental defects and failure in the eeNST transition, which in turn affects larval survival in fish.