Concurrent temporal patterning of neural stem cells in the fly visual system

The temporal and spatial patterning of neural stem cells is a powerful mechanism by which to generate neural diversity in both vertebrate and invertebrate brains. In the Drosophila optic lobe, the neuroblasts (NBs) that generate the [~]120 neuronal cell types of the medulla are patterned by independent temporal and spatial inputs. In the temporal axis, a cascade of twelve transcription factors (TFs) are expressed in medulla NBs as they age. In the spatial axis, the neuroepithelium from which these NBs are generated is sub-divided into eight compartments by the expression of five additional TFs. Distinct neuronal types are generated by NBs based on their spatio-temporal address. Here, we describe a third major patterning axis that further diversifies neuronal fates in the medulla. We show that the symmetrically dividing neuroepithelial cells from which the medulla NBs are generated are temporally patterned by opposing gradients of the Imp and Syp RNA-binding proteins. Imp and Syp regulate the expression of a set of TFs in the neuroepithelium to confer NBs from the same spatio-temporal address with unique identities based on the developmental stage they are generated. We show that Imp and Syp differentially pattern NBs in the Vsx1-Hth spatio-temporal birth window to generate seven distinct neuronal cell types (Li2, TmY17, TmY15, Tm23, Pm3a, Pm3b and TmY12) in successive developmental windows. We further demonstrate that the birthdate of these neurons correlates with their final position in the adult cortex, resulting in unanticipated specializations of the retinotopic circuit in the anterior-posterior axis of the visual system. The concurrent temporal patterning of symmetrically and asymmetrically dividing neural stem cells thus acts as a powerful mechanism to couple the generation of neural diversity with circuit patterning.