Abstract
Purpose: :
To identify the role of the atypical cadherin Fat3 during amacrine cell (AC) development using mouse genetics. Newly born ACs migrate to their final positions in the inner nuclear layer (INL) or ganglion cell layer (GCL) and extend dendrites into the inner plexiform layer (IPL). Since in other systems the Fat cadherins regulate analogous tissue patterning and cellular polarization events we propose that Fat3 has a similar role during retinal development.
Methods: :
Fat3 knockout (KO) and conditional knockout (CKO) mice were generated targeting a single exon encoding the Fat3 transmembrane domain. In KOs, Fat3 is missing from the entire retina throughout development. For CKOs, Fat3 was removed from ACs by breeding to ptf1a:Cre transgenic mice. Retinas were evaluated by immunofluorescent labeling, confocal microscopy, and in situ hybridization.
Results: :
Neuronal and synaptic lamination is altered in the fat3 KO retina leading to the formation of four plexiform layers. Mutant ACs develop ‘bipolar’ dendritic morphologies by extending additional dendrites away from the IPL. As a result two novel plexiform layers are formed; one that divides the INL and the other within the nerve fiber layer. Despite this formation of the inner and outer plexiform layers appears normal. Fat3 also regulates the distribution of certain classes of ACs between the INL and GCL, and in KOs there is excess AC migration into the GCL. These two events can be separated genetically because AC-specific CKOs have ectopic dendrites but lack the migration phenotype.
Conclusions: :
The atypical cadherin Fat3 coordinates AC morphology and migration during development of the vertebrate retina. These events are regulated by two Fat3 signaling mechanisms functioning in parallel: A cell-autonomous mechanism in ACs that directs dendrite morphology, and a non-autonomous mechanism in GCs that regulates AC migration. Together these data suggest that plexiform layer formation can be initiated by ACs alone while nuclear layer organization depends on Fat3-signaling between GCs and ACs.
Keywords: retinal development • amacrine cells • cell-cell communication