Anterior-Posterior Gradient in Neural Stem and Daughter Cell Proliferation Governed by Spatial and Temporal Hox Control

Abstract

A readily evident feature of animal central nervous systems (CNSs), apparent in all vertebrates and many invertebrates alike, is its "wedge-like" appearance, with more cells generated in anterior than posterior regions. This wedge could conceivably be established by an antero-posterior (A-P) gradient in the number of neural progenitor cells, their proliferation behaviors, and/or programmed cell death (PCD). However, the contribution of each of these mechanisms, and the underlying genetic programs, are not well understood. Building upon recent progress in the Drosophila melanogaster (Drosophila) ventral nerve cord (VNC), we address these issues in a comprehensive manner. We find that, although PCD plays a role in controlling cell numbers along the A-P axis, the main driver of the wedge is a gradient of daughter proliferation, with divisions directly generating neurons (type 0) being more prevalent posteriorly and dividing daughters (type I) more prevalent anteriorly. In addition, neural progenitor (NB) cell-cycle exit occurs earlier posteriorly. The gradient of type I > 0 daughter proliferation switch and NB exit combine to generate radically different average lineage sizes along the A-P axis, differing by more than 3-fold in cell number. We find that the Hox homeotic genes, expressed in overlapping A-P gradients and with a late temporal onset in NBs, trigger the type I > 0 daughter proliferation switch and NB exit. Given the highly evolutionarily conserved expression of overlapping Hox homeotic genes in the CNS, our results point to a common mechanism for generating the CNS wedge.

Neural Lineage Progression Controlled by a Temporal Proliferation Program

“…Hox regulation: Hox factors are turned on late in NBs (Baumgardt et al, 2014;Karlsson et al, 2010;Monedero Cobeta et al, 2017), and we find that this may be explained by our finding that Wor, Kr, and Pdm2-Nub act as repressors of Antp. On the other hand, Ase and Hb were activators of Antp, which may help explain the precise onset of Antp in late NBs.…”

Multi-level and lineage-specific interactomes of the Hox transcription factor Ubx contribute to its functional specificity

“…9). In contrast, grh IM ;Ubx 1 double heterozygous mutant embryos exhibited additional NBs in A1 and A2 segments, revealing a functional cooperation between Ubx and Grh during programmed cell death 56,58,59 . This interaction is of functional importance only in the neural lineage, as the muscle pattern was unaltered in grh IM ;Ubx 1 double heterozygous mutant embryos ( Supplementary Fig.…”

“…6g, h). Using Dpn stainings as read-out 40,[55][56][57] , we found that single Ubx 1 and grh IM homozygous mutants displayed supernumerary NBs in the A1 segment (Ubx, +4NBs) and in all abdominal segments (Grh), while single heterozygous mutants did not show a significant change in NBs number ( Supplementary Fig. 9).…”

Genetic Mechanisms Regulating the Spatiotemporal Modulation of Proliferation Rate and Mode in Neural Progenitors and Daughter Cells during Embryonic CNS Development

“…2) Cell cycle exit followed by programmed cell death (PCD) e.g., NB5-6T. 3) PCD e.g., NB7-3 [122,123,127,129,130] (Fig. 17).…”

“…In Drosophila CNS lineages, an NB can exit cell cycle by death, or first exit cell cycle and then die. Both modes are employed to trim the lineage and ensure the generation of the right numbers and types of cells [122,130]. proteins Draper and Simu [154,155].…”