A connectome and transcriptome identity shift through a single transcription factor isoform

We integrate analyses of neuronal anatomy, whole-cell electrophysiology, and single-cell RNA sequencing of genetically manipulated neurons (scRNA-Perturb-Seq) to establish that the transcription factor broad functions to control neuronal identity and subsequent wiring programs between two visual projection neuron cell types, LPLC1 and LPLC2. We demonstrate the first characterization in functional connectivity changes following changes in neuronal identity specification.

We find broad acts through a single isoform (broad-z4) that is selectively expressed in LPLC1, and has the capacity to reprogram the morphology, functional connectivity, and transcriptional identity of postmitotic LPLC2 neurons into an LPLC1-like cell type. Our findings establish a single transcription factor isoform as the smallest unit required to differentiate neuronal identity, a strategy that may be conserved within developmental programs to expand the capacity for cell type diversity across animal species.