Credit: GETTY

During the morphogenesis of many organs, simple epithelial tubes stereotypically branch or bend and twist, thus enabling a tissue to take its shape. By combining experimental analysis and computational modelling in mice and flies, two groups now provide insights into the subcellular events that initiate these changes for the tissue as a whole.

In the developing mouse lung, epithelial tubes that form the airway undergo characteristic shape changes. Tang et al. first showed that such changes result from allometric growth, in which the tube length increases more than tube circumference, rather than from alterations in cell size or shape. On closer inspection, the authors found that a significant proportion of epithelial cells divide parallel to the longitudinal axis of the airway, and that both orientation of the mitotic spindle and tube shape are controlled by RAS-regulated extracellular signal-regulated kinase 1 (ERK1; also known as MAPK3) and ERK2 (also known as MAPK1). Hyperactivation of ERK1–ERK2 signalling resulted in the randomization of spindle orientation, leading to isometric tube growth, in which tube length and circumference increased at the same rate. Moreover, the Sprouty family proteins SPRY1 and SPRY2, which inhibit ERK1–ERK2 signalling in other contexts, were important for limiting ERK1–ERK2 signalling downstream of fibroblast growth factor 10 (FGF10) during tube growth.

But can these oriented cell divisions explain the observed airway tube shape change? To address this, Tang et al. used mathematical modelling to predict how changes in the angle of cell division would affect tube shape and found that this is a crucial parameter that is sufficient to explain the allometric growth of the tube. The authors propose that spindles orient longitudinally by default and that changes in the level of ERK1–ERK2 signalling, which are 'reined in' by SPRY1 and SPRY2, alter spindle orientation.

In the second study, Taniguchi et al. focused on the mechanisms that underlie the left-handed rotation of the developing hindgut in Drosophila melanogaster. They first tested how the properties of individual gut epithelial cells might contribute to the asymmetric behaviour of the whole tube, finding that epithelial cells have an asymmetric cell shape with respect to the embryo's left–right axis — a phenomenon that they term planar cell-shape chirality (PCC).

the altered behaviour of single cells ... can drive global tissue morphogenesis.

How might this asymmetric cell shape arise? Myosin ID (MYOID) is important for normal left–right rotation of the gut, and the authors found that MYOID is also important for PCC. They then homed in on D. melanogaster epithelial cadherin (DE-cadherin), a transmembrane regulator of cell–cell adhesion, and showed, through genetic analysis, that DE-cadherin acts downstream of MYOID to control PCC.

Consistent with this, they observed that DE-cadherin is left–right-asymmetrically distributed along the apical boundaries of cells. On the basis of its mutant phenotype, they speculate that DE-cadherin may increase cortical tension asymmetrically, which may in turn promote a left-handed rotation of the whole tissue. Taniguchi et al. also turned to modelling to test the validity of this prediction and found that changes in PCC can account for the left-handed rotation of the gut.

Together, these studies reveal the different ways in which the altered behaviour of single cells — through non-random mitotic spindle orientation or single-cell chirality — can drive global tissue morphogenesis. It will be important to learn more about how these biases are established, as they may be independent of classic planar cell polarity signalling, and whether either mechanism applies to the morphogenesis of other tubular organs.