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, the mechanisms by which maternal lipids are used and regulate embryogenesis remain unclear.

As oviparous models, fish depend entirely on yolk and its 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 successful 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, led by Prof. SUN Yonghua from the Institute of Hydrobiology (IHB) of the Chinese Academy of Sciences, has 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. This study was published in Nature Communications.

In this study, the 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 endogenous to exogenous nutrient sources (eeNST), indicating active lipid remodeling.

Using RNA sequencing, the researchers identified 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，the researchers found that a deficiency in hsd17b12a impaired LC-PUFA synthesis in the primitive intestine. This deficiency caused defective yolk absorption, failure of swim bladder inflation, and embryonic death, thus preventing a successful eeNST transition. The researchers also observed the structural and functional abnormalities in the primitive intestine and disrupted expansion of digestive organs such as the pancreas and liver.

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

In conclusion, this study reveals a novel mechanism in which the DHA-PA-PG axis in the primitive intestine regulates lipid utilization and organ expansion. 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.

(Editor: MA Yun)