Neurogenic decisions require a cell cycle independent function of the CDC25B phosphatase

Bonnet, Frédéric; Molina, Angie; Roussat, Mélanie; Azais, Manon; Bel-Vialar, Sophie; Gautrais, Jacques; Pituello, Fabienne; Agius, Eric

doi:10.7554/elife.32937

Cited by 16 publications

(64 citation statements)

References 87 publications

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“…For the sake of clarity, we recall here the basic model we designed in Bonnet et al [9]. We consider a population of cells at time t, some of which are proliferating progenitors P (t), and the others are differentiated neurons N (t).…”

Section: Basic Model For the Dynamics Of Mode Of Divisionmentioning

confidence: 99%

“…Following our previous study on the role of a cell cycle regulator, the phosphatase CDC25B, in the control of neurogenesis in the chicken neural tube [9], our question here is to examine whether the progenitors that perform asymmetric neurogenic divisions have lost their proliferative power at some time point (fate restriction).…”

Section: Introductionmentioning

confidence: 99%

“…To give sense to this hypothesis, we start from the model of fate transition we have proposed in our previous paper about the instrumental role CDC25B plays in the progression from proliferative to neurogenic divisions [9]. In the spirit of Lander et al [11], modeling is used here as a way to gain clarity in the face of intricacy.…”

Section: Introductionmentioning

confidence: 99%

“…To this end, we build on the model we have presented in the work reported in [9]. This model considered Mode of Division (hereafter MoD) as stationary over the 24 hours of our experiment.…”

Section: Introductionmentioning

confidence: 99%

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

Azais

Agius

Blanco

et al. 2018

Preprint

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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.

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Section: Basic Model For the Dynamics Of Mode Of Divisionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…To this end, we build on the model we have presented in the work reported in [9]. This model considered Mode of Division (hereafter MoD) as stationary over the 24 hours of our experiment.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Azais

Agius

Blanco

et al. 2018

Preprint

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“…This suggests a cell-cycle independent role for Foxm1 during this process. Cell cycle regulators such as Cdc25b and Ccnd1 have been shown to play a role during neuronal development independently of their primary function [18][19][20]. Thus, it is possible that Foxm1 can promote neuronal differentiation in the regenerating spinal cord without affecting the overall length of the cell cycle.…”

Section: Discussionmentioning

confidence: 99%

Foxm1 regulates neuronal progenitor fate during spinal cord regeneration

Pelzer¹,

Phipps

Thuret³

et al. 2020

Preprint

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Keywords: spinal cord / regeneration / Foxm1 / progenitor / Xenopus / differentiation Pelzer et al. Role of Foxm1 during spinal cord regeneration 2 Summary Mammals have limited tissue regeneration capabilities, particularly in the case of the central nervous system. Spinal cord injuries are often irreversible and lead to the loss of motor and sensory function below the site of the damage [1]. In contrast, amphibians suchas Xenopus tadpoles can regenerate a fully functional tail, including their spinal cord, following amputation [2,3]. A hallmark of spinal cord regeneration is the re-activation of Sox2/3+ progenitor cells to promote regrowth of the spinal cord and the generation of new neurons [4,5]. In axolotls, this increase in proliferation is tightly regulated as progenitors switch from a neurogenic to a proliferative division via the planar polarity pathway (PCP) [6][7][8]. How the balance between self-renewal and differentiation is controlled during regeneration is not well understood. Here, we took an unbiased approach to identify regulators of the cell cycle expressed specifically in X.tropicalis spinal cord after tail amputation by RNAseq. This led to the identification of Foxm1 as a potential key transcription factor for spinal cord regeneration. Foxm1-/-X.tropicalis tadpoles develop normally but cannot regenerate their spinal cords. Using single cell RNAseq and immunolabelling, we show that foxm1+ cells in the regenerating spinal cord undergo a transient but dramatic change in the relative length of the different phases of the cell cycle, suggesting a change in their ability to differentiate. Indeed, we show that Foxm1 does not regulate the rate of progenitor proliferation but is required for neuronal differentiation leading to successful spinal cord regeneration. Pelzer et al. Role of Foxm1 during spinal cord regeneration 3 Results Foxm1 is specifically expressed in the regenerating spinal cordWe compared the transcriptome of isolated spinal cords at 1day post amputation (1dpa) and 3dpa to spinal cord from intact tails (0dpa, Figure 1A). Principle component plot, dendogram of sample-to-sample distances and MA-plot of the log fold change (FC) of expression in relation to the average count confirmed the quality of the data (Figures S1A-D). Between 0dpa and 1dpa, 5129 differentially expressed (DE) transcripts (FC> 2 and FDR<0.01) were identified (2074 down-, 3055 up-regulated). Between 0dpa and 3dpa, 9787 genes are differentially expressed (4609 down and 5178 up-regulated, Figure S1E).To identify the most enriched biological processes by gene ontology (GO), a nonbiased hierarchical cluster for all DE genes was performed ( Figure 1B). We observed three phases: first an increase in expression of genes involved in metabolic processes (cluster I), then a strong upregulation of genes associated with cell cycle regulation (cluster II and III) and finally, a downregulation of expression of genes involved in nervous system development (Cluster IV and V, Figure 1B).Using Ingenuity Pathway Analysis (IPA), we identi...

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Regulation of size and scale in vertebrate spinal cord development

Kuzmicz-Kowalska

Kicheva

2020

WIREs Developmental Biology

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All vertebrates have a spinal cord with dimensions and shape specific to their species. Yet how species‐specific organ size and shape are achieved is a fundamental unresolved question in biology. The formation and sculpting of organs begins during embryonic development. As it develops, the spinal cord extends in anterior–posterior direction in synchrony with the overall growth of the body. The dorsoventral (DV) and apicobasal lengths of the spinal cord neuroepithelium also change, while at the same time a characteristic pattern of neural progenitor subtypes along the DV axis is established and elaborated. At the basis of these changes in tissue size and shape are biophysical determinants, such as the change in cell number, cell size and shape, and anisotropic tissue growth. These processes are controlled by global tissue‐scale regulators, such as morphogen signaling gradients as well as mechanical forces. Current challenges in the field are to uncover how these tissue‐scale regulatory mechanisms are translated to the cellular and molecular level, and how regulation of distinct cellular processes gives rise to an overall defined size. Addressing these questions will help not only to achieve a better understanding of how size is controlled, but also of how tissue size is coordinated with the specification of pattern. This article is categorized under: Establishment of Spatial and Temporal Patterns > Regulation of Size, Proportion, and Timing Signaling Pathways > Global Signaling Mechanisms Nervous System Development > Vertebrates: General Principles

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Neurogenic decisions require a cell cycle independent function of the CDC25B phosphatase

Cited by 16 publications

References 87 publications

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

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

Foxm1 regulates neuronal progenitor fate during spinal cord regeneration

Regulation of size and scale in vertebrate spinal cord development

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