Thus, removing Cdh6 does not disrupt the formation or positioning of OPN neurons, which argues that the defective targeting www.selleckchem.com/products/MLN-2238.html in Cdh6 mutants reflects a failure of specific RGCs to recognize and terminate in their proper targets. We noted variation in the severity of axon targeting defects in Cdh6 mutants, especially at ages P20 and older. In early postnatal animals (P0–P6), 3 out of 11 Cdh3-GFP::Cdh6−/− mice exhibited apparently normal Cdh3-RGC axon targeting. In the remaining 8 Cdh3-GFP::Cdh6−/− mice, the reduction in Cdh3-RGC input to the OPN ranged from severe

(n = 5) to moderate (n = 3). By P20, 3 out of 7 Cdh6−/− mice had no apparent targeting defects, 2 out of seven had severe phenotypes and 2 had moderate phenotypes. Examples of the variation in target innervation defects in the OPN and mdPPN are shown in Figure S4. This variation suggests that other molecules can compensate for early targeting errors caused by removal of Cdh6. One candidate is Cdh3. We attempted to create Cdh3-GFP::Cdh3−/− mice in order to visualize the axons of Cdh3-RGCs in the Cdh3 null background but unfortunately those efforts failed, likely because the Cdh3-GFP transgene and the Cdh3 null cassette are located near one another on the same chromosome. However, whole-eye retinofugal

tracing of Cdh3−/− mutant mice indicated that eye-specific targeting to the dLGN and SC was normal. Input to image-forming areas was also normal in Cdh6−/− mutant mice, as assessed by whole-eye anterograde labeling (Figures 4N–4P). Deciphering the molecular HSP inhibition basis of neural circuit specificity is a longstanding goal of neurobiology. The hypothesis that cadherins generate precise connectivity in the nervous system was

initially put forth by Takeichi and coworkers (Suzuki et al., 1997 and Inoue et al., 1998). Loss-of-function data support that model in lower vertebrates and flies (Inoue and else Sanes, 1997, Lee et al., 2001 and Prakash et al., 2005). Previous studies showed that distinct components of mammalian sensory circuits can be defined by their expression of different cadherins (Suzuki et al., 1997 and Hertel et al., 2008), but evidence that cadherins play a functional role in generating wiring specificity in the mammalian CNS has been lacking. Here, we showed that Cdh6 mediates axon-target matching in a specific non-image-forming visual circuit. These data provide some of the first evidence that a specific classical cadherin can promote wiring specificity in the mammalian visual system. The axon targeting defects we observed in Cdh6 knockout mice raise important questions about the mechanisms by which cadherins impart specificity of neural connections. The simplest explanation is that Cdh6-expressing RGC axons adhere to Cdh6 expressing target neurons via homophilic interactions that occur at the level of the targets.