Biology subjects

Agius, E.

Publications and source records attributed to Agius, E..

4 recordsLinked to original sources

bioRxiv2020

G1 PHASE LENGTHENING DURING NEURAL TISSUE DEVELOPMENT INVOLVES CDC25B INDUCED G1 HETEROGENEITY.

While lengthening of the cell cycle and G1 phase is a generic feature of tissue maturation during development, the underlying mechanism remains still poorly understood. Here we develop a time lapse imaging strategy to measure the four phases of the cell cycle in single neural progenitor cells in their endogenous environment. Our results show that neural progenitors possess a great heterogeneity of the cell cycle length. This duration variability is distributed over all phases of the cell cycle, with the G1 phase being the one contributing primarily to cell cycle variability. Within one cell cycle, each phase duration appears stochastic and independent except for a surprising correlation between S and M phase. Lineage analysis indicates that the majority of daughter cells display longer G1 phase than their mothers suggesting that at each cell cycle a mechanism lengthens the G1 phase. We identify an actor of the core cell cycle machinery, the CDC25B phosphatase known to regulate G2/M transition, as an indirect regulator of the duration of the G1 phase. We propose that CDC25B acts via a cell to cell increase in G1 phase heterogeneity revealing a novel mechanism of G1 lengthening associated with tissue development.

developmental biology↗

bioRxiv2018

Mathematical modeling supports fate restriction in neurogenic progenitors of the embryonic ventral spinal cord

In the developing neural tube in chicken and mammals, neural stem cells proliferate and differentiate according to a stereotyped spatio-temporal pattern. Several actors have been identified in the control of this process, from tissue-scale morphogens patterning (Shh, BMP) to intrinsic determinants in neural progenitor cells. In a previous study (Bonnet et al. eLife 7, 2018), we have shown that the CDC25B phosphatase promotes the transition from proliferation to differentiation in a cell-cycle independent fashion. In this study, we set up a mathematical model linking progenitor modes of division to the dynamics of progenitors and differentiated populations. Here, we build on this previous model to propose a complete dynamical picture of this process. We start from the standard model in which progenitors are homogeneous and can perform any type of divisions (proliferative division yielding two progenitors, asymmetric neurogenic divisions yielding one progenitor and one neuron, and terminal symmetric divisions yielding two neurons). We constraint this model using published data about mode of divisions and population dynamics of progenitors/neurons at different developmental stages (Saade et al. Cell Reports 4, 2013), and check the effect of CDC25B gain of function in this context. Next, we explore the scenarios in which progenitors population is actually split into two different pools, one of which composed of cells that have lost the capacity to perform proliferative divisions (fate restriction). We show that one such scenario appears relevant and calls for further identification of the alternative role of CDC25B in such a fate restriction.

developmental biology↗

bioRxiv2017

FGFs are orchestra conductors of Shh-dependent oligodendroglial fate specification in the ventral spinal cord

Most oligodendrocytes of the spinal cord originate from ventral progenitor cells of the pMN domain, characterized by expression of the transcription factor Olig2. A minority of oligodendrocytes is also recognized to emerge from dorsal progenitors during fetal development. The prevailing view is that generation of ventral oligodendrocytes depends on Sonic hedgehog (Shh) while dorsal oligodendrocytes develop under the influence of Fibroblast Growth Factors (FGFs). Using the well-established model of the chicken embryo, we evidence that ventral spinal progenitor cells activate FGF signaling at the onset of oligodendrocyte precursor cell (OPC) generation, as do they dorsal counterpart. Inhibition of FGF receptors at that time appears sufficient to prevent generation of ventral OPCs, highlighting that, in addition to Shh, FGF signaling is required also for generation of ventral OPCs. We further reveal an unsuspected interplay between Shh and FGF signaling by showing that FGFs serve dual essential functions in ventral OPC specification. FGFs are responsible for timely induction of a secondary Shh signaling center, the lateral floor plate, a crucial step to create the burst of Shh required for OPC specification. At the same time, FGFs prevent down-regulation of Olig2 in pMN progenitor cells as these cells receive higher threshold of the Shh signal. Finally, we bring arguments favoring a key role of newly differentiated neurons acting as providers of the FGF signal required to trigger OPC generation in the ventral spinal cord.

developmental biology↗

bioRxiv2017

Neurogenic decisions require a cell cycle independent function of the CD25B phosphatase

A fundamental issue in developmental biology and in organ homeostasis is understanding the molecular mechanisms governing the balance between stem cell maintenance and differentiation into a specific lineage. Accumulating data suggest that cell cycle dynamics plays a major role in the regulation of this balance. Here we show that the G2/M cell cycle regulator CDC25B phosphatase is required in mammals to finely tune neuronal production in the neural tube. We show that in chick neural progenitors, CDC25B activity is both required and sufficient to stimulate neurogenic divisions and to promote neuronal differentiation. We design a mathematical model showing that within a limited period of time, cell cycle length modifications cannot account for changes in the ratio of the mode of division. Using a CDC25B point mutation that cannot interact with CDK, we show that part of CDC25B activity on neurogenic divisions is independent of its action on the cell cycle.

developmental biology↗