TDP-43 Is Required For Proliferation Of Mammary Epithelial Cells And Mammary Gland Repopulation

Mammary epithelial cells(MECs)are mainly composed of basal and luminal cells.The proliferation of MECs is fundamental to mammary development,and aberrant proliferation has possibility to drive breast cancer.Previously,we identified a crucial regulatory role of TDP-43 in the proliferation of breast cancer cells.TDP-43 belongs to hnRNPs family and can bind to DNA or RNA to regulate gene expression.However,the function of TDP-43 in mammary gland is unclear,further functional exploration will be important in understanding roles in mammary development.Based on single-cell data analysis of the mammary gland,TDP-43 showed potential involvement in the regulation of MaSCs.Our data in mammosphere formation and transplantation assay demonstrated that TDP-43 was required for the mammary gland repopulation and proliferation of MECs.Knockout of TDP-43 in mammary epithelium of K14-CreERT?Tardbpfl/fl mouse reduced mammary ductal branching and inhibited proliferation of MECs.For preliminary exploration of regulatory mechanism,we found that knockdown of TDP-43 led to cell-cycle arrest at the G1 phase.RNA-seq data and other experiments identified that loss of TDP-43 induced the up-regulation of genes related to the cell cycle and the expression of p21 and linc-p21s which activates p21,providing a possible mechanism for TDP-43 in regulating MECs.In conclusion,our findings indicate a previously unknown role of TDP-43 in repopulation and proliferation of MECs and ductal morphogenesis,and we also explore the preliminary regulatory mechanism.