Progenitor properties of symmetrically dividing Drosophila neuroblasts during embryonic and larval development.

Asymmetric cell division generates two daughter cells of differential gene expression and/or cell shape. Drosophila neuroblasts undergo typical asymmetric divisions with regard to both features; this is achieved by asymmetric segregation of cell fate determinants (such as Prospero) and also by asymmetric spindle formation. The loss of genes involved in these individual asymmetric processes has revealed the roles of each asymmetric feature in neurogenesis, yet little is known about the fate of the neuroblast progeny when asymmetric processes are blocked and the cells divide symmetrically. We genetically created such neuroblasts, and found that in embryos, they were initially mitotic and then gradually differentiated into neurons, frequently forming a clone of cells homogeneous in temporal identity. By contrast, larval neuroblasts with the same genotype continued to proliferate without differentiation. Our results indicate that asymmetric divisions govern lineage length and progeny fate, consequently generating neural diversity, while the progeny fate of symmetrically dividing neuroblasts depends on developmental stages, presumably reflecting differential activities of Prospero in the nucleus.

Robustness under functional constraint: the genetic network for temporal expression in Drosophila neurogenesis.

Precise temporal coordination of gene expression is crucial for many developmental processes. One central question in developmental biology is how such coordinated expression patterns are robustly controlled. During embryonic development of the Drosophila central nervous system, neural stem cells called neuroblasts express a group of genes in a definite order, which leads to the diversity of cell types. We produced all possible regulatory networks of these genes and examined their expression dynamics numerically. From the analysis, we identified requisite regulations and predicted an unknown factor to reproduce known expression profiles caused by loss-of-function or overexpression of the genes in vivo, as well as in the wild type. Following this, we evaluated the stability of the actual Drosophila network for sequential expression. This network shows the highest robustness against parameter variations and gene expression fluctuations among the possible networks that reproduce the expression profiles. We propose a regulatory module composed of three types of regulations that is responsible for precise sequential expression. This study suggests that the Drosophila network for sequential expression has evolved to generate the robust temporal expression for neuronal specification.

Neuroblast entry into quiescence is regulated intrinsically by the combined action of spatial Hox proteins and temporal identity factors.

Neural stem cell quiescence is an important feature in invertebrate and mammalian central nervous system development, yet little is known about the mechanisms regulating entry into quiescence, maintenance of cell fate during quiescence, and exit from quiescence. Drosophila neural stem cells (called neuroblasts) provide an excellent model system for investigating these issues. Drosophila neuroblasts enter quiescence at the end of embryogenesis and resume proliferation during larval stages; however, no single neuroblast lineage has been traced from embryo into larval stages. Here, we establish a model neuroblast lineage, NB3-3, which allows us to reproducibly observe lineage development from neuroblast formation in the embryo, through quiescence, to the resumption of proliferation in larval stages. Using this new model lineage, we show a continuous sequence of temporal changes in the neuroblast, defined by known and novel temporal identity factors, running from embryonic through larval stages, and that quiescence suspends but does not alter the order of neuroblast temporal gene expression. We further show that neuroblast entry into quiescence is regulated intrinsically by two independent controls: spatial control by the Hox proteins Antp and Abd-A, and temporal control by previously identified temporal transcription factors and the transcription co-factor Nab.

Maintaining youth in Drosophila neural progenitors.

An important question is how dividing stem cells maintain competence to generate multiple cell types, whereas most other cells become progressively restricted during development. The molecular basis for progenitor competence--or how competence is progressively restricted--has remained mysterious. Recent work has shown that Drosophila neuroblasts and mammalian neural progenitors are more similar than previously appreciated, and provide an excellent model system for using Drosophila genetics to unravel the molecular nature of progenitor competence and how it becomes progressively restricted during development.