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H, H9 and Table 1), with fewer projections failing to quit in the normal medulla termination web-sites. The penetrance of pathfinding, defasciculation, and termination defects in 40h pupae was reduced in Pten than in Tsc1 null mutant photoreceptors projecting to a wild-type CNS (Table 1). In sum, Pten and Tsc1 mutant photoreceptor projections show distinct patterns of photoreceptor axon guidance defects, regardless of the truth that these two inhibitors of Tsc-Rheb-Tor signaling have related influences on cell size, growth, and differentiation [202,246,28]. We also observed distinct effects of Tsc1 and Pten retinal mosaics on the differentiation of lamina neurons and visual system glia, detected with anti-Dachshund and anti-Repo antibodies, respectively (Figure S1). Pten mutant retinal projections created an abnormally big lamina not noticed in Tsc1 mosaics (Figure S1AC). In each Pten and Tsc1 mosaics visual technique glia were discovered within the brain in roughly standard positions (Figure S1D), though some disorganization was evident in brains receiving Tsc1 mutant photoreceptor projections. It really is possible that this disruption of glial architecture might partially contribute towards the axon projection defects observed in Tsc1 mutants.To evaluate the effects of lowered Tor signaling, we examined axon guidance in animals bearing hypomorphic mutations in Tor and Rheb, also as a null allele of S6k, a key downstream target of TORC1. In all three of these mutants, mild axon projection defects have been observed (Figure 6A, Table 1). Third instar larvae had irregular laminas and abnormally thick projections to the medulla (Figure 6A, arrowheads). In 40 h pupae, R7 and R8 terminations have been largely typical, but there have been projections which misrouted and failed to terminate properly (Figure 6D, Table 1). Genetic mosaic evaluation of Rheb mutant photoreceptor projections showed A massive difference in tetraspanin expression was also observed in between keratinocytes from the very same donor in their proliferative point out , and in their non-proliferative, differentiated state precisely the same phenotypes, demonstrating that standard levels of Tor-Tsc signaling in the retina are required for right photoreceptor targeting (data not shown). These findings establish that reductions in Tor-Tsc signaling also make axon guidance defects, though fairly mild in comparison to activation of the pathway accomplished by loss of Tsc1 function. Nevertheless, only the S6k mutants are null in these experiments, and we cannot hence fully assess the contributions of Tor or Rheb to axon guidance in comparison to Tsc1. To determine if the functional relationships important for development control are also in impact for axon guidance, we carried out genetic epistasis experiments between Tsc1 and each Tor and S6k. Tsc1 mosaic pupae show severe axon guidance abnormalities and Tsc1 mutant animals usually do not survive for the pupal stage; in contrast, animals bearing both a Tsc1 mutation and a hypomorphic Tor allele survived to pupal stages and showed only modest axon guidance abnormalities in larval and pupal brains (Figure 6G, H, Table 1). The gross disruptions of R7/R8 terminations in the medullas of 40h Tsc1 mosaic pupae have been nearly totally rescued by the presence of a hypomorphic allele of Tor. Genetic mosaics with Tsc1 Rheb double mutant chromosomes also showed dramatic rescue of photoreceptor axon guidance defects wild-type controls with rapamycin made only mild defects in the lamina plexus (Figure 7D, Table 1) supporting the hypothesis that Tsc1-mediated regulation of axon guidance operates largely through a rapamycin-insensitive function of Tor.