Kindlin-2 in myoepithelium controls luminal progenitor commitment to alveoli in mouse mammary gland.
Kindlin-2 in myoepithelium controls luminal progenitor commitment to alveoli in mouse mammary gland.
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DOI：
10.1038/s41419-023-06184-2
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发表时间：
2023-10-13
影响因子：
9
通讯作者：
Zhang, Hongquan
中科院分区：
文献类型：
--
作者：
Wang, Zhenbin;Zhang, Lei;Li, Bing;Song, Jiagui;Yu, Miao;Zhang, Jing;Chen, Ceshi;Zhan, Jun;Zhang, Hongquan
肌上皮在乳腺发育中发挥着重要作用，但人们对肌上皮如何控制妊娠期间腺泡分化的分子机制知之甚少。在此，我们发现肌上皮细胞中 Kindlin-2 的缺失会损害乳腺形态发生、肺泡发生和泌乳。使用五个转基因小鼠品系并结合单细胞 RNA 测序，我们在肌上皮细胞中发现了 Kindlin-2–Stat3–Dll1 信号级联，它使管腔细胞中的 Notch 信号失活，从而驱动管腔祖细胞对肺泡细胞身份的承诺。单细胞分析显示 Kindlin-2 缺失显着降低了成熟肺泡细胞的比例。从机制上讲，肌上皮细胞中 Kindlin-2 的缺失会促进 Stat3 激活并上调 Dll1，从而激活管腔细胞中的 Notch 通路并抑制妊娠期间管腔祖细胞的分化和成熟。在肌上皮中 Kindlin-2 缺失的怀孕小鼠中，用橘子素抑制 Notch1 可以使管腔祖细胞重新获得承诺能力。综上所述，我们证明 Kindlin-2 对于妊娠期间肌上皮控制的管腔祖细胞向肺泡的转变至关重要。
Myoepithelium plays an important role in mammary gland development, but less is known about the molecular mechanism underlying how myoepithelium controls acinus differentiation during gestation. Herein, we found that loss of Kindlin-2 in myoepithelial cells impaired mammary morphogenesis, alveologenesis, and lactation. Using five genetically modified mouse lines combined with single-cell RNA sequencing, we found a Kindlin-2–Stat3–Dll1 signaling cascade in myoepithelial cells that inactivates Notch signaling in luminal cells and consequently drives luminal progenitor commitment to alveolar cells identity. Single-cell profiling revealed that Kindlin-2 loss significantly reduces the proportion of matured alveolar cells. Mechanistically, Kindlin-2 depletion in myoepithelial cells promotes Stat3 activation and upregulates Dll1, which activates the Notch pathway in luminal cells and inhibits luminal progenitor differentiation and maturation during gestation. Inhibition of Notch1 with tangeretin allowed luminal progenitors to regain commitment ability in the pregnant mice with Kindlin-2 depletion in myoepithelium. Taken together, we demonstrated that Kindlin-2 is essential to myoepithelium-controlled luminal progenitors to alveoli transition during gestation.
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