Coordination between stochastic and deterministic specification in the Drosophila visual system

INTRODUCTION Neuronal fate decisions must be coordinated across brain regions so that the proper stoichiometry of distinct afferents and their target neurons is established. Many sensory systems rely on stochastic fate specification to increase their repertoire of neuronal types and/or to establish the mosaic of distinct sensory receptors. Once these stochastic fate decisions have been made at the periphery, they must be conveyed to processing centers in the brain to ensure that the correct information is retained. This in turn requires that the proper number of target neurons of the proper type are generated and are connected to their cognate sensory receptors. How these stochastically determined sensory systems transmit their decision to their targets in the brain—as when red (L) and green (M) cone photoreceptors connect to their appropriate bipolar cells in the human retina, or when randomly specified olfactory receptors project to their correct glomeruli in the mouse olfactory bulb—has remained unknown. RATIONALE In the Drosophila retina, different types of color-sensitive R7 photoreceptors with different ultraviolet spectral sensitivities are stochastically specified and distributed. By contrast, neurogenesis of the optic lobes that receive input from photoreceptors is highly deterministic: A fixed number of neuroblasts produces sequentially the same types of neurons following a rigid temporal program as well as a spatial program of determination. We asked how the stochastic choices made in the retina are propagated to the optic lobes—that is, how stochastically specified photoreceptors project and connect to their neuronal targets that are generated through a highly deterministic program. RESULTS We identified distinct subtypes of the main postsynaptic target of the ultraviolet-sensitive R7 photoreceptors, the Dm8 neurons. Each Dm8 subtype is specific to one of the three different subtypes of R7, and their organization in the optic lobe mirrors the topographic organization of R7s in the retina. The three subtypes of Dm8 are prespecified early in neurogenesis by distinct neural progenitors, independently from (and before) any photoreceptor input. These neurons are produced in excess, but only when the correct photoreceptor-Dm8 pairs form do Dm8s survive. This allows them to accommodate random variations in the production of the subtypes of R7s. Those Dm8s that do not find their correct R7 partner are culled by programmed cell death. We then showed that matching of one of the R7-Dm8 subtypes is mediated by two complementary cell adhesion molecules: Dpr11 in one of the subtypes of R7, and its cognate receptor DIPγ in the corresponding subclass of Dm8. Loss of either molecule leads to the death of that Dm8 subtype or its mispairing with the wrong R7 subtype; these phenotypes are similar to the loss of the corresponding subtype of R7 photoreceptors. These mechanisms allow the qualitative and quantitative matching of R7 subtypes with their target in the brain, and thus permit the stochastic choice made in R7 to be propagated to the deterministically specified downstream circuit to support color vision. CONCLUSION Our data reveal two fundamental principles in circuit formation: (i) The neurotrophic theory suggests that neuronal survival depends on trophic factors provided by the targets. We show that apoptosis is also involved in the quantitative and qualitative matching of target neurons with their afferent sensory receptors, providing a direct link between correct synaptic partner choice and cell survival. (ii) As Sperry’s chemoaffinity theory proposed, we show that synaptic partner choice is controlled by two interacting cell adhesion molecules, which are part of two large families of interacting proteins.