Control of cell proliferation in the embryonic CNS by Temporal, Hox and Notch cues. Stefan Thor. Dept Clinical and Exp Medicine, Linkoping Univ, Linkoping, OG, Sweden.

   Substantial progress has been made with respect to cell fate specification in the nervous system. In contrast, less is known regarding the control of proliferation, such that proper numbers of each neural cell type is generated. In the embryonic Drosophila nerve cord, neuroblasts (NBs) generate the CNS by dividing asymmetrically, renewing themselves while budding off daughter cells, the ganglion mother cells (GMC). Each GMC in turn divides asymmetrically to produce two different neurons and/or glia. This is denoted a Type I division mode, because daughters divide once. The transcription factor Prospero plays a key role in controlling daughter cell proliferation in Type I daughters (GMCs). Recent studies have identified an alternate division mode, where NBs bud off daughters that directly differentiate. We propose that this division mode should be denoted Type 0, since daughter cells do not divide. However, the extent of Type I and Type 0 proliferation in the CNS, and the extent to which NBs display switches in the proliferation modes were hitherto unknown. By mapping several specific NB lineages, and conducting a global analysis of division mode, we find that half of all NB lineages in the nerve cord undergo a Type I to Type 0 switch. While Pros controls Type I daughter proliferation, Pros does not control Type 0 daughter proliferation. Instead, the switch from Type I to Type 0 mode is combinatorially controlled by the temporal genes castor and grainyhead, the Hox gene Antennapedia and Notch signaling. These regulatory cues all emerge in the latter part of many lineages, thus ensuring proper temporal control of the Type I to Type 0 switch. Analysis of 22 key cell cycle genes reveals that the dacapo gene (p21CIP/p27KIP) is the key player triggering the Type I to Type 0 switch. Dacapo expression is triggered late in switching lineages by the temporal, Hox and Notch cues, and ectopic expression of the regulatory cues or Dacapo is sufficient to trigger the proliferation switch. These findings reveal a novel global principle for proliferation control in the Drosophila CNS.