The butyrophilin 1a1 knockout mouse revisited: Ablation of Btn1a1 leads to concurrent cell death and renewal in the mammary epithelium during lactation.
The butyrophilin 1a1 knockout mouse revisited: Ablation of Btn1a1 leads to concurrent cell death and renewal in the mammary epithelium during lactation.
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DOI：
10.1096/fba.2021-00059
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发表时间：
2021-12
影响因子：
2.7
通讯作者：
Mather IH
中科院分区：
文献类型：
--
作者：
Jeong J;Kadegowda AKG;Meyer TJ;Jenkins LM;Dinan JC;Wysolmerski JJ;Weigert R;Mather IH
亲丁酸蛋白1A1 （BTN1A1）作为一种膜受体参与乳腺上皮细胞的脂滴分泌，并与氧化还原酶黄嘌呤氧化还原酶（XDH）形成分泌复合物。BTN1A1在这一过程中起作用的第一个证据是BTN1A1 - / -小鼠系的产生，其中脂质分泌被破坏，大的不稳定液滴被释放到具有破碎表面膜的肺泡间隙中。我们使用RNAseq和蛋白质组学分析重新研究了其中一个突变小鼠系，以评估切除Btn1a1基因对其他基因和蛋白质表达的影响。破坏完整的Btn1a1蛋白表达导致细胞质中Xdh的大量积累，诱导急性期反应基因和Stat3磷酸化的生命激活。在哺乳期高峰期，大约。通过核DNA TUNEL分析，10%的细胞死亡。可能的细胞死亡途径包括caspase 8和活化的caspase 3的表达、自噬、Slc5a8介导的survivin失活（Birc5）和pStat3介导的溶酶体裂解，后者是野生型细胞的主要死亡途径。分泌上皮的更新延长了乳汁的分泌时间，这一点可以从大约1。细胞周期蛋白和Fos/Jun的表达。这些数据强调了乳腺上皮的可塑性，以及BTN1A1功能性表达对于维持终末分化分泌细胞和哺乳期间最佳产奶量的重要性。
Butyrophilin 1A1 (BTN1A1) is implicated in the secretion of lipid droplets from mammary epithelial cells as a membrane receptor, which forms a secretion complex with the redox enzyme, xanthine oxidoreductase (XDH). The first evidence that BTN1A1 functions in this process was the generation of Btn1a1 −/− mouse lines, in which lipid secretion was disrupted and large unstable droplets were released into alveolar spaces with fragmented surface membranes. We have revisited one of these mutant mouse lines using RNAseq and proteomic analysis to assess the consequences of ablating the Btn1a1 gene on the expression of other genes and proteins. Disruption of intact Btn1a1 protein expression led to a large build‐up of Xdh in the cytoplasm, induction of acute phase response genes and Lif‐activation of Stat3 phosphorylation. At peak lactation, approx. 10% of the cells were dying, as assessed by TUNEL‐analysis of nuclear DNA. Possible cell death pathways included expression of caspase 8 and activated caspase 3, autophagy, Slc5a8‐mediated inactivation of survivin (Birc5), and pStat3‐mediated lysosomal lysis, the latter of which is the principal death route in involuting wild type cells. Milk secretion was prolonged by renewal of the secretory epithelium, as evidenced by the upregulation of Ki67 in approx. 10% of cell nuclei and expression of cyclins and Fos/Jun. These data highlight the plasticity of the mammary epithelium and the importance of functional BTN1A1 expression for maintenance of terminally differentiated secretory cells and optimal milk production throughout lactation.