Alveolar progenitor differentiation and lactation depends on paracrine inhibition of notch via ROBO1/CTNNB1/JAG1.
Alveolar progenitor differentiation and lactation depends on paracrine inhibition of notch via ROBO1/CTNNB1/JAG1.
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DOI：
10.1242/dev.199940
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发表时间：
2021-11-01
期刊：
影响因子：
--
通讯作者：
Hinck L
中科院分区：
文献类型：
--
作者：
Cazares O;Chatterjee S;Lee P;Strietzel C;Bubolz JW;Harburg G;Howard J;Katzman S;Sanford J;Hinck L
在乳腺中，肺泡祖细胞如何在每个发情周期和妊娠中被募集以促进组织生长仍然知之甚少。在这里，我们确定了一个调节途径，控制肺泡祖细胞分化和哺乳期的管理Notch激活小鼠。乳腺上皮中Robo 1的缺失激活Notch信号传导，其以肺泡分化为代价扩大肺泡祖细胞群，导致泌乳受损。ROBO 1在管腔和基底细胞中表达，但基底细胞中Robo 1的缺失导致管腔分化缺陷。在基底室中，ROBO 1通过调节与Jag 1启动子结合的β-连环蛋白（CTNNB 1）来抑制Notch配体Jag 1的表达。总之，我们的研究揭示了ROBO 1/CTTNB 1/JAG 1信号传导在基底室中如何对腔室中的Notch信号传导施加旁分泌控制，以调节妊娠期间的肺泡分化。总结：这项研究表明，基底上皮细胞中的Robo 1/β-catenin/JAG 1信号传导调节管腔Notch活性和肺泡祖细胞分化，提供了一种非激素方式来靶向产奶和缓解泌乳不足。
In the mammary gland, how alveolar progenitor cells are recruited to fuel tissue growth with each estrus cycle and pregnancy remains poorly understood. Here, we identify a regulatory pathway that controls alveolar progenitor differentiation and lactation by governing Notch activation in mouse. Loss of Robo1 in the mammary gland epithelium activates Notch signaling, which expands the alveolar progenitor cell population at the expense of alveolar differentiation, resulting in compromised lactation. ROBO1 is expressed in both luminal and basal cells, but loss of Robo1 in basal cells results in the luminal differentiation defect. In the basal compartment, ROBO1 inhibits the expression of Notch ligand Jag1 by regulating β-catenin (CTNNB1), which binds the Jag1 promoter. Together, our studies reveal how ROBO1/CTTNB1/JAG1 signaling in the basal compartment exerts paracrine control of Notch signaling in the luminal compartment to regulate alveolar differentiation during pregnancy. Summary: This study demonstrates that Robo1/β-catenin/JAG1 signaling in basal epithelial cells regulates luminal Notch activity and alveolar progenitor differentiation, offering a non-hormonal way to target milk production and mitigate lactation insufficiency.
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