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

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

doi:10.1038/s41467-019-14183-1

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.

Highlights

Milk lipid secretion is a critical process for the delivery of nutrition and energy from parent to offspring
We show that TDP-43 could bind to the 3′untranslated regions (UTRs) of the Btn1a1 and Xdh transcripts and thereby regulate their messenger RNA stability
Despite some studies suggesting that post-transcriptional regulation of lactation is important[23,24], little information is currently available on the functional roles of regulators on lactation at the post-transcriptional level

Summary

Introduction

Milk lipid secretion is a critical process for the delivery of nutrition and energy from parent to offspring. 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. RNA-binding proteins (RBPs) mediate key steps in post-transcriptional regulation of gene expression[25,26,27]. Identifying those RBPs that control the post-transcriptional expression of essential genes in lactation would be helpful for delineating the milk secretion process. We show that TDP-43 could bind to the 3′untranslated regions (UTRs) of the Btn1a1 and Xdh transcripts and thereby regulate their messenger RNA (mRNA) stability. Our findings highlight the crucial role of TDP-43 in milk lipid secretion

Methods

Results

Conclusion