TDP-43 facilitates milk lipid secretion by post-transcriptional regulation of Btn1a1 and Xdh

Limin Zhao, Hao Ke, Haibo Xu, Guo Dong Wang, Honglei Zhang, Li Zou, Shu Xiang, Mengyuan Li, Li Peng, Mingfang Zhou, Lingling Li, Lei Ao, Qin Yang, Che Kun James Shen, Ping Yi, Lu Wang, Baowei Jiao

Research output: Contribution to journalArticlepeer-review

Abstract

Milk lipid secretion is a critical process for the delivery of nutrition and energy from parent to offspring. However, the underlying molecular mechanism is less clear. Here we report that TDP-43, a RNA-binding protein, underwent positive selection in the mammalian lineage. Furthermore, TDP-43 gene (Tardbp) loss induces accumulation of large lipid droplets and severe lipid secretion deficiency in mammary epithelial cells to outside alveolar lumens, eventually resulting in lactation failure and pup starvation within three weeks postpartum. In human milk samples from lactating women, the expression levels of TDP-43 is positively correlated with higher milk output. Mechanistically, TDP-43 exerts post-transcriptional regulation of Btn1a1 and Xdh mRNA stability, which are required for the secretion of lipid droplets from epithelial cells to the lumen. Taken together, our results highlights the critical role of TDP-43 in milk lipid secretion, providing a potential strategy for the screening and intervention of clinical lactation insufficiency.

Original languageEnglish
Article number341
JournalNature Communications
Volume11
Issue number1
DOIs
Publication statusPublished - Dec 1 2020
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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