Cyclin E Acts under the Control of Hox-Genes as a Cell Fate Determinant in the Developing Central Nervous System

Abstract

The mechanisms controlling the generation of cell diversity in the central nervous system belong to the major unsolved problems in developmental biology. The fly Drosophila melanogaster is a suitable model system to examine these mechanisms at the level of individually identifiable cells. Recently, we have provided evidence that CyclinE-largely independent of its role in cell proliferation-plays a critical role in the specification of neural stem cells (neuroblasts). CycE specifies neuronal fate within neuroblast lineages by acting upstream of glial factors (prospero and glial cell missing), whereby levels of CycE are controlled by homeotic genes, the master control genes regulating segment specific development. Considering the general relevance of CycE and homeotic genes in developing organisms, it seems likely that this mechanism has been conserved among species to contribute to regional diversification in the CNS. EARLY NEUROGENESIS IN DROSOPHILAGeneration of diverse cell types from a common precursor cell within one or two of its divisions is still a relatively less understood problem. Although asymmetric localization of certain gene products explains part of the events, it is not clear if there is a direct link between cell-cycle regulation and cell fate determination. Specification of cell fates and generation of cell diversity in the central nervous system is a good model system in studies attempting to link cell-cycle regulation and cell fate determination.The embryonic central nervous system (CNS) in insects develops from a bilateral, two-dimensional sheet of cells, the neuroectoderm, from which multipotent stem cells, the neuroblasts (NBs), delaminate ( Fig. 1A and B). 1 Through the expression of proneural genes of the Achaete-Scute-Complex at precise locations, groups of neuroectodermal cells, called proneural clusters, acquire the potential to become NBs (e.g., refs. 2 and 4) Cell-cell interactions, mediated by the neurogenic genes, achieve that in each proneural cluster only a single cell with the highest level of proneural gene expression adopts a NB fate, while the others remain in the periphery to develop as epidermoblasts. 5 The singling out of NBs follows a stereotype spatial and temporal pattern. 1,6 Upon delamination NBs typically undergo repeated asymmetric divisions, budding off smaller ganglion mother cells, which divide once to produce neurons and/or glial cells. 7 By this each NB produces a specific cell lineage (Fig. 1C). 8,9 The fate of the individual NBs depends on their position within the neuroectoderm, 10,11 time of delamination, 12 and the combination of genes they express. 6,13

Cell Cycle Defects Contribute to a Block in Hormone-induced Mammary Gland Proliferation in CCAAT/Enhancer-binding Protein (C/EBPβ)-null Mice

“…Overexpression of cyclin E results in accelerated entry into S phase and may lead to polyploidy and genomic instability in cancer cells by this mechanism. In addition, homeotic genes have been shown to control the levels of cyclin E as an important step in regulating asymmetric division of neural stem cells in Drosphila (38). Therefore, it is interesting to speculate that loss of cyclin E expression in C/EBP␤-null mammary cells may have additional consequences, such as an alteration in cell fate.…”

Subtypes of glial cells in the Drosophila embryonic ventral nerve cord as related to lineage and gene expression

“…However, some of these serially homologous lineages develop characteristic, tagma-specific differences with regard to cell number and/or cell types (Udolph et al, 1993;Bossing et al, 1996a;Bossing et al, 1996b;Schmidt et al, 1997). Tagma-specific characteristics of these lineages have been shown to be under the control of Hox genes (Prokop and Technau 1994;Berger et al, 2005).…”

Downstream of Homeotic Genes: In the Heart of Hox function

“…A very similar situation has been recently described in the neuronal lineage NB6-4 of abdominal segments, where abdA suppresses neuroblast asymmetric divisions through repression of Cyclin E (CycE). 50 Ubx shows the same ability. However, CycE does not appear to play any function in cardiac cell fate, as CycE loss-or gain-of-function do not influence cell lineage choice (Monier B, Perrin L, Sémériva M, unpublished observations), indicating that another unknown mechanism is at work in the cardiac tube.…”