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…
Fat4 and Dachsous cadherins are large proteins that govern tissue growth and cell arrangement across various species. In humans, Fat4 interacts with Dchs1, but its association with Dchs2 remains uncertain. This study reveals that Dchs2 binds Fat4 in a trans-heterophilic manner, similar to the Fat4-Dchs1 relationship. During the growth of a mouse retina, Fat4 and Dchs1 show peak expression during embryonic stages and taper off after birth, while Dchs2 commences postnatally and remains active throughout adulthood.
All three proteins are expressed concurrently from birth up to the second week postnatally. Notably, mice lacking Dchs2 exhibit augmented cone numbers, reduced Muller glia count, and disorganized photoreceptor outer segments. Electron microscope images demonstrate that retinal photoreceptors lacking Dchs2 fail to form the orderly nuclear columns observed in normal samples, with disrupted stacking and breaks in the outer limiting membrane.
These results establish Dchs2 as a unique Fat4 ligand and reveal a specialized, non-redundant role for Dchs2 in organizing photoreceptors and maintaining the outer limiting membrane integrity in the adult retina.
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