Strickland Phyllis, Shin Grace C, Plump Andrew, Tessier-Lavigne Marc, Hinck Lindsay
Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, 95064, USA.
Development. 2006 Mar;133(5):823-32. doi: 10.1242/dev.02261. Epub 2006 Jan 26.
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 Robo1 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.
包括乳腺在内的许多器官的发育都涉及导管形态发生。乳腺导管是双层管状结构，由外层的帽状/肌上皮细胞（MEC）和内层的腔上皮细胞（LEC）组成。Slit2在两层细胞中均有表达，分泌的SLIT2广泛分布于整个上皮区室。相比之下，Robo1仅由帽状/MEC特异性表达。Slit2和Robo1的功能丧失突变产生相似的表型，其特征是末端芽（EB）紊乱，类似于Ntn1（-/-）腺体中的情况，这表明SLIT2和NTN1在乳腺发育过程中协同发挥作用。对Slit2（-/-）；Ntn1（-/-）腺体的分析显示出一种增强的表型，这种表型贯穿导管，其特征是细胞层分离和管腔闭塞。聚集试验表明，与野生型细胞相比，Slit2（-/-）；Ntn1（-/-）细胞不能形成双层类器官，添加SLIT2可挽救这一缺陷。单独使用NTN1没有效果，但能协同增强这种挽救作用。因此，我们的数据确立了SLIT2作为一种黏附信号的新作用，它与NTN1并行发挥作用，在双层管形成过程中沿导管生成细胞边界。
