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Coordinated control of neuronal differentiation and wiring by sustained transcription factors

ABSTRACT: The large diversity of cell types in nervous systems presents a challenge in identifying the genetic mechanisms that encode it. Here, we report that nearly 200 distinct neurons in the Drosophila visual system can each be defined by unique combinations of on average 10 continuously expressed transcription factors. We show that targeted modifications of this terminal selector code induce predictable conversions of neuronal fates that appear morphologically and transcriptionally complete. Cis-regulatory analysis of open chromatin links one of these genes to an upstream patterning factor that specifies neuronal fates in stem cells. Experimentally validated network models describe the synergistic regulation of downstream effectors by terminal selectors and ecdysone signaling during brain wiring. Our results provide a generalizable framework of how specific fates are implemented in postmitotic neurons.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE199734 | GEO | 2022/04/01

REPOSITORIES: GEO

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A global timing mechanism regulates cell-type specific wiring programs

Project description:The assembly of neural circuits is dependent upon precise spatiotemporal expression of cell recognition molecules1–6. Factors controlling cell-type specificity have been identified7–9, but how timing is determined remains unknown. Here we describe the induction of a cascade of transcription factors by a steroid hormone (Ecdysone) in all fly visual system neurons spanning target recognition and synaptogenesis. We demonstrate through single cell sequencing that the Ecdysone pathway regulates the expression of a common set of targets required for synaptic maturation and cell-type specific targets enriched for cell surface proteins regulating wiring specificity. Transcription factors in the cascade regulate the expression of the same wiring genes in complex ways, including activation in one cell-type and repression in another. We show that disruption of the Ecdysone-pathway generates specific defects in dendritic and axonal processes and synaptic connectivity, with the order of transcription factor expression correlating with sequential steps in wiring. We also identify shared targets of a cell-type specific transcription factor and the Ecdysone pathway which regulate specificity. We propose neurons integrate a global temporal transcriptional module with cell-type specific transcription factors to generate different cell-type specific patterns of cell recognition molecules regulating wiring.

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