The Drosophila protocadherin Fat (Ft) regulates growth, planar cell polarity (PCP) and proximodistal patterning. A key downstream component of Ft signaling is the atypical myosin Dachs (D). Multiple regions of the intracellular domain of Ft have been implicated in regulating growth and PCP but how Ft regulates D is not known. Mutations in Fbxl7, which encodes an F-box protein, result in tissue overgrowth and abnormalities in proximodistal patterning that phenocopy deleting a specific portion of the intracellular domain (ICD) of Ft that regulates both growth and PCP. Fbxl7 binds to this same portion of the Ft ICD, co-localizes with Ft to the proximal edge of cells and regulates the levels and asymmetry of D at the apical membrane. Fbxl7 can also regulate the trafficking of proteins between the apical membrane and intracellular vesicles. Thus Fbxl7 functions in a subset of pathways downstream of Ft and links Ft to D localization.
Multi-cellular organisms are made up of cells that are organized into tissues and organs that reach a predictable size and shape at the end of their development. To do this, cells must be able to sense their position and orientation within the body and know when to stop growing.
Epithelial cells—which make up the outer surface of an animal's body and line the cavities of its internal organs—connect to each other to form flat sheets. These sheets of cells contain structures that are oriented along the plane of the sheet. However, how this so-called ‘planar cell polarity’ coordinates with cell growth in order to build complex tissues and organs remains to be discovered.
A protein called Fat is a major player in both planar cell polarity and the Hippo signaling pathway, which controls cell growth. As such, the Fat protein appears to be crucial for controlling the size and shape of organs. Mutations in the Fat protein cause massive tissue overgrowth, prevent planar cell polarity being established correctly, and stop the legs and wings of fruit flies developing normally.
The Fat protein also plays a role in distributing another protein called Dachs—which is also part of the Hippo signaling pathway. In epithelial cells of the developing wing, Dachs is mostly located on the side of the cell that is closest to the tip of the developing wing (the so-called ‘distal surface’). How Fat and Dachs work together is not understood, but it is known that they do not bind to each other directly.
Now, Bosch et al. show that in the fruit fly Drosophila, the Fat protein binds to another protein called Fbxl7. Flies that cannot produce working Fbxl7 have defects in some aspects of planar cell polarity and a modest increase in tissue growth. Fbxl7 seems to account for part, but not all, of the ability of Fat to restrict tissue growth. Furthermore, a lack of the Fbxl7 protein results in a spreading of Dachs protein across the apical surface—which faces out of the epithelial sheet—of epithelial cells. On the other hand, if Fbxl7 is over-expressed, Dachs is driven to the interior of each cell. Hence, a normal level of Fbxl7 protein restricts the Dachs protein to the correct parts of the cell surface.
Together, the findings of Bosch et al. show that the Fbxl7 protein is a key link between the Fat and Dachs proteins. These results also provide an understanding of how growth and planar cell polarity—two processes that are essential for normal development of all multi-cellular organisms—are coordinated.