Fat cadherins are emerging as highly versatile molecules that act through multiple pathways to regulate diverse aspects of cell behavior (Sopko and BTK inhibitor McNeill, 2009). Our results reveal still more functions for Fat cadherins, establishing independent roles in neuronal morphogenesis and cell migration. Although the effects on AC morphology likely involve regulation of the cytoskeleton, how Fat3 signaling in RGCs ultimately cordons ACs in the INL is unclear. However, a non-autonomous function for Fat has been suggested in flies, where Fat may regulate transcription of secreted factors essential for PCP, possibly through the transcriptional repressor Atrophin (Fanto et al.,

2003). Similarly, Fat3 might act in RGCs to control production of a chemorepellent that prevents ACs from

migrating through the IPL. selleck chemicals llc The nature of the fat3KO phenotype provides an excellent example of how mutations in one gene can create new cellular layers that are associated with equally discrete synaptic layers, as likely occurred during the evolution of the nervous system. Indeed, even a relatively subtle change in neuronal morphology such as the retention of a trailing process is apparently sufficient to drive development of an entirely new plexiform layer. In addition, certain neurons seem to serve as master regulators of circuit assembly, and our findings support emerging models of retinal development in which maturation of the IPL is guided by ACs ( Mumm et al., 2005). Thus, when AC development is disrupted, the overall structure of the retina is as well. Notably, despite the presence of two additional plexiform layers and extra cells in the GCL, the overall organization of the retina is not severely disrupted: the basic layers are present and the new layers are neatly organized. This suggests that the retina is quite plastic in its ability to accommodate changes in the organization and shapes of ACs.

Thus, although mutations in critical regulators of cell already fate and proliferation lead to catastrophic failure of brain development, the fat3 phenotype demonstrates that single gene changes can also generate orderly changes in the structure of the nervous system. This provides a potential explanation for how expanded populations of neurons can be incorporated into pre-existing circuits without compromising animal viability. Fat3 mutant mice were generated by homologous recombination in ES cells followed by breeding to Cre or FLPe transgenic mice. Additional details are provided in Supplemental Experimental Procedures. Fat3KO and fat3floxed lines were maintained by backcross to B6129PF1/J mice (Jackson Laboratory, Bar Harbor, ME). Transgenic mice came from the following sources: ACTB-Cre, Thy1::YFP-H, Z/EG (Jackson Laboratory); ACTB-FLPe (S. Dymecki, Harvard Medical School); Fjx1 (A. Vortkamp, U. Duisburg-Essen); Ptf1a-cre (C.