Hedgehog and Spitz: Making a Match between Photoreceptor Axons and Their Targets

Three additional levels of complexity in lamina structure suggest that matching the numbers of R cell axons to lamina neurons is only the first of a series of interactions between afferent axons and lamina cells. First, lamina neurons adopt one of five different fates. Different lamina neurons are arranged in a characteristic spatial pattern with respect to the R cell axons (reviewed in Meinertzhagen and Hanson 1993xSee all ReferencesMeinertzhagen and Hanson 1993). Second, the optic lobe contains multiple types of glial cells whose development must be coordinated with differentiation of the lamina neurons. Finally, a precise pattern of synaptic contacts must be elaborated between R cell axons and their target neurons.How are individual lamina neuron fates determined? One possibility is that SPI and HH are the only signals produced by retinal axons that are required to establish the normal complement of neuronal fates. In this view, perhaps differences in the spatial or temporal patterns of SPI and HH release followed by lateral interactions between lamina neurons and the adjacent glia create differences between presumptive lamina neurons. By analogy with the mechanisms required for R cell fate determination in the eye (Freeman 1997xFreeman, M. Development. 1997; 124: 261–270PubMedSee all ReferencesFreeman 1997), dynamic expression of EGFR and Argos could establish regulatory loops controlling lamina patterning. Alternatively, additional signals might be released by retinal axons, either from all R1–R6 axons or from specific R cell subsets, to specify different lamina neuron fates. In this view, spatial patterning might be generated through a series of stereotyped contacts between R cell growth cones and developing lamina neurons. Resolution of these possibilities will require additional molecular markers specific to each lamina neuron fate and the identification of additional genes regulating this process.Lamina glia depend on retinal innervation to migrate and differentiate (Perez and Steller 1996xPerez, S.E and Steller, H. J. Neurobiol. 1996; 30: 359–373Crossref | PubMed | Scopus (71)See all ReferencesPerez and Steller 1996). R1–R6 growth cones terminate between two specific layers of glial cells in the lamina, the epithelial and marginal glia. These glial cells migrate to their specific positions from two precursor zones located at the dorsal and ventral edges of the lamina. Since lamina glial cell development is independent of both HH and EGFR (Huang and Kunes 1998xHuang, Z and Kunes, S. Development. 1998; 125: 3753–3764PubMedSee all ReferencesHuang and Kunes 1998), R cell axons probably provide a third signal to the target area to induce glial cell maturation.Dialog between R cell axons and their targets also occurs in the context of establishing the correct pattern of neuronal connections. While R cell axons provide signals during larval development that pattern the target, the target region produces guidance cues to ingrowing R cell axons. These cues ensure that R cell axons terminate in the correct layer of the optic lobe and are arranged in a topographically appropriate manner. At the onset of pupal development, R1–R6 growth cones leave their original lamina column and project in a precise pattern to neighboring columns such that R cells that “look at the same point in space” select the same target neurons. This process creates the adult cartridge and requires at least one additional signal, lamina-derived nitric oxide (Gibbs and Truman 1998xGibbs, S.M and Truman, J.E. Neuron. 1998; 20: 83–93Abstract | Full Text | Full Text PDF | PubMed | Scopus (168)See all ReferencesGibbs and Truman 1998). This signal allows R cell axons to remain within the lamina and correctly identify their targets. Once this reorganization is complete, R cell axons and lamina neurons initiate a complex, characteristic pattern of synaptogenesis. Work in other systems suggests that such patterns are coordinated by bidirectional signaling between pre- and postsynaptic cells.Recent work on NT-3 and brain-derived neurotrophic factor suggests that anterograde transport of developmental signals regulating target development may be widespread (e.g., von Bartheld et al. 1996xvon Bartheld, C.S, Byers, M.R, Williams, R, and Bothwell, M. Nature. 1996; 379: 830–833Crossref | PubMed | Scopus (238)See all Referencesvon Bartheld et al. 1996). Moreover, mammalian HH and EGF homologs are expressed in the developing retina (e.g., 10xLillien, L and Cepko, C. Development. 1992; 115: 253–266PubMedSee all References, 9xJensen, A.M and Wallace, V.A. Development. 1997; 124: 363–371PubMedSee all References), raising the possibility that the mechanisms that coordinate retinal innervation with target development in Drosophila might also apply to the mammalian visual system. However, while matching the numbers of afferent axons to target cells is an important first step in constructing a functional nervous system, solving the matching problem at the levels of specificity seen in the mature synaptic circuitry remains one of the central challenges in developmental neurobiology.