In the Drosophila optic lobes, ~200 types of neurons organized as 800 columns process the inputs from 800 unit-eyes. We study how this variety of neurons is generated during development and how connectivity among these neurons is regulated

            The ~800 Neural stem cells in the medulla sequentially express a series of temporal transcription factors (tTFs), producing in each temporal window different neurons that innervate each of the 800 columns. At each division, the neural stem cell produces an intermediate precursor that divides once, producing a NotchON and a NotchOFF neuron.

            We used single-cell mRNA sequencing to identify the complete series of tTFs that specify most optic lobe neurons from birth to adulthood. Each tTF regulates the progression of the series by activating the next tTF and repressing the previous one. This allowed us to establish the temporal window of origin and birth order of each neuronal type in the medulla. These tTFs are sufficient to explain the generation of the entire neuronal diversity in this brain region by integrating temporal and spatial patterning as well as their Notch status.

            We discovered that the 250 distinct neurons in the Drosophila visual system can be defined by unique combinations of ~10 ‘terminal selector’ TFs that are continuously expressed in each neuron from birth to adulthood. Targeted modifications of this ‘selector’ code induce predictable conversions of cell fates between neurons that appear to be morphologically and transcriptionally complete. Using single nuclei ATAC-seq data (Aerts lab), we showed that Cis-regulatory sequences link this ‘selector’ program to the upstream tTFs that specify neuronal fates. This provides a generalizable framework of how specific fates are initiated and maintained in postmitotic neurons.

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