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 () and Baowei Jiao ()
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Limin Zhao: Chinese Academy of Sciences
Hao Ke: Chinese Academy of Sciences
Haibo Xu: Chinese Academy of Sciences
Guo-Dong Wang: Chinese Academy of Sciences
Honglei Zhang: Chinese Academy of Sciences
Li Zou: Chinese Academy of Sciences
Shu Xiang: Calmette International Hospital
Mengyuan Li: The Third Affiliated Hospital of Chongqing Medical University
Li Peng: Yubei District Maternal and Child Health Care Hospital
Mingfang Zhou: The Third Affiliated Hospital of Chongqing Medical University
Lingling Li: Chinese Academy of Sciences
Lei Ao: Kunming Angel Women’s and Children’s Hospital
Qin Yang: Chinese Academy of Sciences
Che-Kun James Shen: Academia Sinica
Ping Yi: The Third Affiliated Hospital of Chongqing Medical University
Lu Wang: Yunnan University
Baowei Jiao: Chinese Academy of Sciences

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-019-14183-1

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