Combinatorial action of Grainyhead, Extradenticle and Notch in regulating Hox mediated apoptosis in Drosophila larval CNS

Hox mediated neuroblast apoptosis is a prevalent way to pattern larval central nervous system (CNS) by different Hox genes, but the mechanism of this apoptosis is not understood. Our studies with Abdominal-A (Abd-A) mediated larval neuroblast (pNB) apoptosis suggests that AbdA, its cofactor Extradenticle (Exd), a helix-loop-helix transcription factor Grainyhead (Grh), and Notch signaling transcriptionally contribute to expression of RHG family of apoptotic genes. We find that Grh, AbdA, and Exd function together at multiple motifs on the apoptotic enhancer. In vivo mutagenesis of these motifs suggest that they are important for the maintenance of the activity of the enhancer rather than its initiation. We also find that Exd function is independent of its known partner homothorax in this apoptosis. We extend some of our findings to Deformed expressing region of sub-esophageal ganglia where pNBs undergo a similar Hox dependent apoptosis. We propose a mechanism where common players like Exd-Grh-Notch work with different Hox genes through region specific enhancers to pattern respective segments of larval central nervous system.
Author summary Specification of the head to tail axis of the developing central nervous system is carried out by Hox genes. Hox mediated programmed cell death of the neural progenitor cells plays an important role in specification of this axis, but the molecular mechanism of this phenomenon is not well understood. We have studied this phenomenon in abdominal and subesophageal regions of larval central nervous system of Drosophila. We find that different Hox genes use a combination of common players (Extradenticle, Grainyhead and Notch) but employ region specific enhancers to cause progenitor cell death in different segments of developing central nervous system.