Twists and Turns in Developing Tubes

Science Signaling  19 Jul 2011:
Vol. 4, Issue 182, pp. ec197
DOI: 10.1126/scisignal.4182ec197

Epithelial tubes form the basis of many tissues and organs, including the lung, kidney, gut, and heart. Asymmetries with respect to the major body axes are often important in the development and function of such organs, so understanding how epithelial tubes bend and twist is important for elucidating morphogenesis of tube-based structures. Two studies examine the mechanical basis and molecular regulation of epithelial tube size and shape. Tang et al. examined the mechanisms that regulate branch length and circumference in the developing mouse lung, in which tube length increases faster than circumference without changes in cell shape or size. This pattern of allometric growth correlated with a bias in mitotic spindle orientation, with a large portion of the cells dividing parallel to the long axis of the tube. Increasing the activity of extracellular signal–regulated kinases (ERKs) 1 and 2 abrogated allometric growth and eliminated the bias in mitotic spindle orientation. Furthermore, knocking out Sprouty 1 (Spry1) and Spry2, which encode negative regulators of fibroblast growth factor (FGF)–induced ERK signaling, also led to abnormal tube morphology and loss of mitotic spindle orientation bias, suggesting that FGF-mediated activation of ERK signaling was responsible for the observed growth and spindle orientation phenomena. Genetic interaction experiments identified FGF10 as the relevant FGF ligand in this context of lung development. Mathematical modeling revealed that the observed mitotic spindle bias could account for the observed growth dynamics in both normal and ERK-activated contexts. In a related study, Taniguchi et al. explored the mechanism by which the hindgut of the fruit fly rotates to the left to create a rightward bend during development. The authors found that the epithelial cells that make this bend have an inherent polarity that the authors called “planar cell-shape chirality” (PCC) along the left-right (LR) axis prior to the rotation and that PCC was reversed in embryos lacking Myo1D, in which the hindgut rotates to the right rather than to the left. Drosophila E-cadherin (DE-Cad) was also required for proper LR asymmetry of the hindgut and was enriched on the left side of hindgut epithelial cells, and this polarity was also reversed in embryos lacking Myo1D. Because Myo1D and DE-Cad restricted the expansion of cell boundaries, the authors proposed that greater tension on the left side of the hindgut epithelial cells was directly responsible for driving the leftward rotation, a hypothesis that was supported by computational modeling. As discussed in a Perspective by Horne-Badovinac and Munro, these studies illustrate the power of combining computational modeling with in vivo observations and experimentation for elucidating the complex morphogenesis of critical tissues and organs.

S. Horne-Badovinac, E. Munro, Tubular transformations. Science 333, 294–295 (2011). [Abstract] [Full Text]

N. Tang, W. F. Marshall, M. McMahon, R. J. Metzger, G. R. Martin, Control of mitotic spindle angle by the RAS-regulated ERK1/2 pathway determines lung tube shape. Science 333, 342–345 (2011). [Abstract] [Full Text]

K. Taniguchi, R. Maeda, T. Ando, T. Okumura, N. Nakazawa, R. Hatori, M. Nakamura, S. Hozumi, H. Fujiwara, K. Matsuno, Chirality in planar cell shape contributes to left-right asymmetric epithelial morphogenesis. Science 333, 339–341 (2011). [Abstract] [Full Text]