Dchs2, a novel Fat4 ligand, is required for photoreceptor organization and outer limiting membrane integrity in the mouse retina

Fat and Dachsous cadherins are large transmembrane proteins that regulate tissue growth and planar cell polarity across species. In mammals, Fat4 is known to bind Dchs1, but whether it also binds Dchs2 is unclear. Here we show that Dchs2 binds Fat4 in a trans-heterophilic manner at cell-cell contacts, mirroring the Fat4-Dchs1 interaction. In the developing mouse retina, Fat4 and Dchs1 expression peaks embryonically and declines after birth, whereas Dchs2 expression begins postnatally and persists into adulthood, with all three co-expressed from birth through the second postnatal week. While Fat4 and Dchs1 mutants show no defects in retinal lamination or cell-type composition, loss of Dchs2 increases number of cones, reduces Muller glia number, and results in disorganization of photoreceptor outer segments. Electron microscopy shows that Dchs2 mutant photoreceptors fail to form the regular nuclear columns seen in controls, with disrupted stacking and breaks in the outer limiting membrane. These findings identify Dchs2 as a novel Fat4 ligand and reveal a distinct, non-redundant requirement for Dchs2 in photoreceptor organization and outer limiting membrane integrity in the mature retina.