But how can Netrin, which is a secreted molecule, be restricted to a
single layer? The authors hypothesize that Netrin can be bound to Fra on surfaces of cells in the target area and is presented as an active complex to incoming R8 axons. To test this idea, the authors deleted Fra only from neurons in the R8 target area and observed the loss of the layer-specific localization of Netrin. Furthermore, expression of membrane-tethered Netrin can completely rescue the Netrin mutant phenotype, demonstrating that Netrin acts KU 55933 locally rather than as a long-range diffusible molecule in this context. In line with these findings, several previous studies demonstrated that Netrin can act as a “membrane-captured” protein. For example, in the fly
embryonic nervous system, Fra binds to and redistributes Netrin, which instructs the guidance both of pioneer neurons and commissural axons ( Hiramoto et al., 2000 and Brankatschk and Dickson, 2006). Furthermore, Unc-40/Fra-captured Netrin mediates dendrite self-avoidance in C. elegans ( Smith et al., 2012), suggesting that this mode of Netrin function is widely used for different tasks in various species. In summary, Timofeev et al. (2012) provide the first evidence that Netrin plays an important role in layer-specific targeting, serving to trap incoming photoreceptor axons in the correct layer. Moreover, Regorafenib mouse they extend previous work by showing that Netrin not only acts as a graded signal over long distances, but can also be locally captured many and presented by Fra to function over short distances. Thus, by identifying a new role for these proteins, as well as a new mechanism for their action, these studies significantly extend our understanding of the versatility of these molecules. Future studies should address how the Netrin/Fra system interacts with other molecules that are also required for R8 targeting, such as Flamingo, Golden Goal, and
Capricious. At a higher level, a critical question concerns the relationship between layer-specific targeting and synaptic specificity. R8 makes only a subset of its synaptic connections within the M3 layer; thus, layer-specific targeting is clearly only part of the story (Takemura et al., 2008). However, it remains possible that the synapses that do form in M3 are promoted by Net-Fra interactions, and hence it becomes important to know which cell types in the M3 layer capture Netrin. Could these cells be synaptic targets of R8? The answer to this question will address whether layer-specific targeting and synapse specificity are always two molecularly distinct processes or whether they can be achieved by the same set of molecules. “
“How our brains learn and remember, and the way in which specific brain structures are involved in memory, are fundamental questions in neuroscience. The key role of cortical regions within the medial temporal lobes (MTL), including the hippocampus and perirhinal cortex, is undisputed.