Abstract
Neuronal precursor cells undergo self-renewing and non-self-renewing asymmetric divisions to generate a large number of neurons of distinct identities. In Drosophila, primary precursor neuroblasts undergo a varying number of self-renewing asymmetric divisions, with one known exception, the MP2 lineage, which undergoes just one terminal asymmetric division similar to the secondary precursor cells. The mechanism and the genes that regulate the transition from self-renewing to non-self-renewing asymmetric division or the number of times a precursor divides is unknown. Here, we show that the T-box transcription factor, Midline (Mid), couples these events. We find that in mid loss of function mutants, MP2 undergoes additional self-renewing asymmetric divisions, the identity of progeny neurons generated dependent upon Numb localization in the parent MP2. MP2 expresses Mid transiently and an over-expression of mid in MP2 can block its division. The mechanism which directs the self-renewing asymmetric division of MP2 in mid involves an upregulation of Cyclin E. Our results indicate that Mid inhibits cyclin E gene expression by binding to a variant Mid-binding site in the cyclin E promoter and represses its expression without entirely abolishing it. Consistent with this, over-expression of cyclin E in MP2 causes its multiple self-renewing asymmetric division. These results reveal a Mid-regulated pathway that restricts the self-renewing asymmetric division potential of cells via inhibiting cyclin E and facilitating their exit from cell cycle.
Highlights
The broad problem of how the division potential of cells is controlled during development is highly significant
Midline regulates the division potential of neural precursors the activity of a gene called midline, precursors such as MP2 that normally divides into two neurons, self-renews and generates a neuron at the same time
The way Midline protein works is that it represses the cyclin E gene via binding to sites in its promoter, preventing the over-expression of Cyclin E and blocking cells from entering the cell cycle
Summary
The broad problem of how the division potential of cells is controlled during development is highly significant. The regulation of the division potential of neural precursors, and their asymmetric division, with or without self-renewal, are fundamental processes that govern the formation of a functional CNS in all animals. While we have made much progress in understanding the biology of stemness and asymmetric division of precursor cells [reviewed in ref. 6], almost nothing is known about the regulation of division potential, a process of great importance. Too few or too many divisions of precursor cells will leave the CNS aberrant and dysfunctional. We sought to use the development of the CNS in Drosophila as a paradigm to study both the regulation of division potential and how this is tied to precursor cell asymmetric division
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