Slit2 and netrin 1 act synergistically as adhesive cues to generate tubular bi-layers during ductal morphogenesis
Slit2 and netrin 1 act synergistically as adhesive cues to generate tubular bi-layers during ductal morphogenesis
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DOI：
10.1242/dev.02261
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发表时间：
2006-03-01
期刊：
影响因子：
4.6
通讯作者：
Hinck, L
中科院分区：
文献类型：
--
作者：
Strickland, P;Shin, GC;Hinck, L
包括乳腺在内的许多器官的发育都涉及导管形态的形成。乳腺导管是双层管状结构，包括外层的帽/肌上皮细胞（MECs）和内层的管腔上皮细胞（LECs）。Slit2在两层细胞中表达，分泌的Slit2广泛分布于上皮腔室。相比之下，Robo1是由cap/ mec特异性表达的。Slit2和Robol的功能缺失突变产生相似的表型，其特征是无组织的端芽（EBs），使人联想到Ntn1（-/-）腺中存在的端芽（EBs），这表明Slit2和Ntn1在乳房发育过程中协同作用。Slit2（-/-）分析；Ntn1（-/-）腺体表现出一种增强的表型，其延伸穿过导管，其特征是细胞层分离和管腔闭塞。聚集分析显示，Slit2(-/-)；与野生型细胞相比，Ntn1（-/-）细胞不形成双层类器官，这是通过添加SLIT2修复的缺陷。NTN1单独不起作用，但协同作用增强了这种拯救。因此，我们的数据确定了SLIT2作为粘附线索的新作用，在双层管形成过程中与NTN1平行作用，沿管道产生细胞边界。
Development of many organs, including the mammary gland, involves ductal morphogenesis. Mammary ducts are bi-layered tubular structures comprising an outer layer of cap/myoepithelial cells (MECs) and an inner layer of luminal epithelial cells (LECs). Slit2 is expressed by cells in both layers, with secreted SLIT2 broadly distributed throughout the epithelial compartment. By contrast, Robo1 is expressed specifically by cap/MECs. Loss-of-function mutations in Slit2 and Robol yield similar phenotypes, characterized by disorganized end buds (EBs) reminiscent of those present in Ntn1(-/-) glands, suggesting that SLIT2 and NTN1 function in concert during mammary development. Analysis of Slit2(-/-);Ntn1(-/-) glands demonstrates an enhanced phenotype that extends through the ducts and is characterized by separated cell layers and occluded lumens. Aggregation assays show that Slit2(-/-);Ntn1(-/-) cells, in contrast to wild-type cells, do not form bi-layered organoids, a defect rescued by addition of SLIT2. NTN1 has no effect alone, but synergistically enhances this rescue. Thus, our data establish a novel role for SLIT2 as an adhesive cue, acting in parallel with NTN1 to generate cell boundaries along ducts during bi-layered tube formation.