Regulation of neuronal subtype cell numbers by POU-domain factor integration of Notch and Hox cell death programs

The precise assembly of functional neural circuits requires tight control over the number and identity of each neuronal subtype. Programmed cell death (PCD) is a key mechanism that eliminates excess or inappropriately specified cells during development. In the Drosophila embryonic ventral nerve cord, the number of Va-Capa neuropeptidergic neurons is controlled by two distinct PCD events: Notch-dependent elimination of the Va-Capa sibling cells, and segment-specific PCD of Va-Capa neurons in posterior segments, triggered by the Hox homeotic gene Abd-B. However, how these two genetic cues regulate PCD in the same neuronal lineage was unknown. Here, we deploy a targeted genetic screen and identify the POU-domain transcription factor Ventral veins lacking (Vvl) as an essential shared regulator of both pathways. Loss of vvl function prevents PCD of the Va-Capa sibling cell in segments A2-A6 and of Va-Capa neurons in A5-A6, resulting in their survival. Conversely, Vvl misexpression is sufficient to induce caspase-dependent PCD of Va-Capa neurons. Genetic epistasis experiments position Vvl downstream of Notch signaling and upstream of the pro-apoptotic gene reaper. In addition, Vvl enhances Abd-B-mediated PCD in segments where Abd-B expression is weak, consistent with a role as a Hox Frontier Assistant. Our results demonstrate that Vvl acts as a common transcriptional effector that integrates Notch dependent and Hox dependent pro-PCD cues to control lineage- and segment-specific neuronal numbers. To our knowledge, Vvl is the first identified factor required for both Notch- and Hox-dependent PCD in postmitotic neurons of the Drosophila central nervous system. These findings reveal a novel molecular mechanism by which a single transcription factor ensures the precise sculpting of neuronal populations during development.