Big roles for Fat cadherins

Abstract

To create an intricately patterned and reproducibly sized and shaped organ, many cellular processes must be tightly regulated. Cell elongation, migration, metabolism, proliferation rates, cell-cell adhesion, planar polarization and junctional contractions all must be coordinated in time and space. Remarkably, a pair of extremely large cell adhesion molecules called Fat (Ft) and Dachsous (Ds), acting largely as a ligand-receptor system, regulate, and likely coordinate, these many diverse processes. Here we describe recent exciting progress on how the Ds-Ft pathway controls these diverse processes, and highlight a few of the many questions remaining as to how these enormous cell adhesion molecules regulate development.

Figure 1

The regulation of Hippo. mitochondrial and PCP activity by the ICDs of Ds and Ft. Details on connections between the Ft ICD and the myosin Dachs are show in Figure 2.

Figure 2

Regulation of Dachs levels and localization by the ICD of Ft. (a) Removal of Ft or Fbxl7 increases Dachs levels in the subapical cell cortex. Removal of Dlish or App reduces Dachs in the subapical cortex and increases cytoplasmic Dachs, even in the absence of Ft. (b) The Ft ICD recruits the F-box ubiquitin ligase to the subapical cell cortex where it reduces Dachs levels, possibly through ubiquination of Dachs or a Dachs binding partner, leading to destabilization of Dachs or trafficking of Dachs away from the cortex. In ft mutants, Dachs levels increase, inhibiting Wts. (c) App and App-palmitoylated Dlish bind and tether Dachs to the subapical cell cortex. Loss of Dlish or App decreases subapical Dachs, disinhibiting Wts. Ft may sequester Dlish or App from Dachs; loss of Ft increases tethering of Dachs, inhibiting Wts.

Figure 3

Dt and Fs in PCP. (a) Cell-by-cell polarization of Ds and Ft binding leads to reduction of Dachs in the side of the cell with higher Ft, and attraction of Dachs and Sple to the side of the cell with higher Ds. (b) Slight initial differences in the polarity of Ds-Ft binding is amplified, both across cell junctions and by across single cells. (c) Loss of Ft mispolarizes Ds and increases the levels of unpolarized Dachs, leading to the mispolarization of Sple and thus disruption of information conveyed by the core PCP pathway.