Howard Hughes Medical Institute, Department of Pediatrics, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colorado, United States of America.
PLoS One. 2012;7(9):e44871. doi: 10.1371/journal.pone.0044871. Epub 2012 Sep 17.
The lung is a complex system in biology and medicine alike. Whereas there is a good understanding of the anatomy and histology of the embryonic and adult lung, less is known about the molecular details and the cellular pathways that ultimately orchestrate lung formation and affect its health. From a forward genetic approach to identify novel genes involved in lung formation, we identified a mutated Nubp1 gene, which leads to syndactyly, eye cataract and lung hypoplasia. In the lung, Nubp1 is expressed in progenitor cells of the distal epithelium. Nubp1(m1Nisw) mutants show increased apoptosis accompanied by a loss of the distal progenitor markers Sftpc, Sox9 and Foxp2. In addition, Nubp1 mutation disrupts localization of the polarity protein Par3 and the mitosis relevant protein Numb. Using knock-down studies in lung epithelial cells, we also demonstrate a function of Nubp1 in regulating centrosome dynamics and microtubule organization. Together, Nubp1 represents an essential protein for lung progenitor survival by coordinating vital cellular processes including cell polarity and centrosomal dynamics.
肺在生物学和医学中都是一个复杂的系统。虽然人们对胚胎期和成人期肺的解剖结构和组织学有了很好的了解，但对分子细节和最终协调肺形成并影响其健康的细胞途径知之甚少。通过正向遗传学方法鉴定参与肺形成的新基因，我们鉴定出一个突变的 Nubp1 基因，该基因导致并指畸形、眼白内障和肺发育不全。在肺中，Nubp1 在远端上皮的祖细胞中表达。Nubp1(m1Nisw) 突变体显示细胞凋亡增加，同时失去远端祖细胞标记物 Sftpc、Sox9 和 Foxp2。此外，Nubp1 突变会破坏极性蛋白 Par3 和有丝分裂相关蛋白 Numb 的定位。通过肺上皮细胞的敲低研究，我们还证明了 Nubp1 在调节中心体动力学和微管组织中的功能。总之，Nubp1 通过协调包括细胞极性和中心体动力学在内的重要细胞过程，代表了肺祖细胞存活所必需的蛋白质。
