Biology subjects

Thuret, R.

Publications and source records attributed to Thuret, R..

4 recordsLinked to original sources

bioRxiv2023

Bmp9 regulates Notch signaling and the temporal dynamics of angiogenesis via Lunatic Fringe

In briefThe mechanisms regulating the signaling pathways involved in angiogenesis are not fully known. Ristori et al. show that Lunatic Fringe (LFng) mediates the crosstalk between Bone Morphogenic Protein 9 (Bmp9) and Notch signaling, thereby regulating the endothelial cell behavior and temporal dynamics of their identity during sprouting angiogenesis. HighlightsO_LIBmp9 upregulates the expression of LFng in endothelial cells. C_LIO_LILFng regulates the temporal dynamics of tip/stalk selection and rearrangement. C_LIO_LILFng indicated to play a role in hereditary hemorrhagic telangiectasia. C_LIO_LIBmp9 and LFng mediate the endothelial cell-pericyte crosstalk. C_LI Bone Morphogenic Protein 9 (Bmp9), whose signaling through Activin receptor-like kinase 1 (Alk1) is involved in several diseases, has been shown to independently activate Notch target genes in an additive fashion with canonical Notch signaling. Here, by integrating predictive computational modeling validated with experiments, we uncover that Bmp9 upregulates Lunatic Fringe (LFng) in endothelial cells (ECs), and thereby also regulates Notch activity in an inter-dependent, multiplicative fashion. Specifically, the Bmp9-upregulated LFng enhances Notch receptor activity creating a much stronger effect when Dll4 ligands are also present. During sprouting, this LFng regulation alters vessel branching by modulating the timing of EC phenotype selection and rearrangement. Our results further indicate that LFng can play a role in Bmp9-related diseases and in pericyte-driven vessel stabilization, since we find LFng contributes to Jag1 upregulation in Bmp9-stimulated ECs; thus, Bmp9-upregulated LFng results in not only enhanced EC Dll4-Notch1 activation, but also Jag1-Notch3 activation in pericytes.

developmental biology↗

bioRxiv2020

Active Perception during Angiogenesis: Filopodia speed up Notch selection of tip cells in silico and in vivo

How do cells make efficient collective decisions during tissue morphogenesis? Humans and other organisms utilize feedback between movement and sensing known as sensorimotor coordination or active perception to inform behaviour, but active perception has not before been investigated at a cellular level within organs. Here we provide the first proof of concept in silico/in vivo study demonstrating that filopodia (actin-rich, dynamic, finger like cell-membrane protrusions) play an unexpected role in speeding up collective endothelial decisions during the time-constrained process of tip cell selection during blood vessel formation (angiogenesis). We first validate simulation predictions in vivo with live imaging of zebrafish intersegmental vessel growth. Further simulation studies then indicate the effect is due to the coupled positive feedback between movement and sensing on filopodia conferring a bistable switch-like property to Notch lateral inhibition, ensuring tip selection is a rapid and robust process. We then employ measures from computational neuroscience to assess whether filopodia function as a primitive ( basal) form of active perception and find evidence in support. By viewing cell behaviour in tissues through the basal cognitive lens we acquire a fresh perspective on not only the well-studied tip cell selection process, revealing a hidden, yet vital, time-keeping role for filopodia, but on how to interpret and understand cell behaviour in general, opening up a myriad of new and exciting research directions.

cell biology↗

bioRxiv2020

Foxm1 regulates neuronal progenitor fate during spinal cord regeneration

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 such as 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) [6-8]. 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.

developmental biology↗

bioRxiv2018

Positive-feedback defines the timing and robustness of angiogenesis

Blood vessel formation by angiogenesis is critical for tissue development, homeostasis and repair, and is frequently dysregulated in disease[1-3]. Angiogenesis is triggered by vascular endothelial growth factor receptor-2/3 (VEGFR) signalling, which induces motile endothelial cell (ECs) tip identity[4,5]. Tip cells lead new branching vessels, but also coordinate collective EC movement by repressing tip identity in adjacent ECs via Delta-Like 4 (DLL4)-Notch-mediated down-regulation of VEGFR activity[6-13]. Hence, angiogenesis is driven by lateral inhibition-mediated competition of ECs for migratory status. Recent work reveals that temporal modulation of this DLL4-Notch-mediated lateral inhibition circuit fundamentally shapes both normal and pathological angiogenesis[14-17]. However, the core regulatory network defining the timing and dynamics of EC decision-making is unclear. Here, by integrating computational modeling with in-vivo experimentation, we uncover a unique ultrasensitive switch that temporally defines EC lateral inhibition and ultimately determines the timing, magnitude and robustness of angiogenic responses. We reveal that positive-feedback to Vegfr via the atypical tetraspanin, tm4sf18, amplifies Vegfr activity and expedites EC decision-making in-vivo. Moreover, this Tm4sf18-mediated positive-feedback confers robustness to angiogenesis against changeable environmental conditions by invoking bistable-like behavior. Consequently, mutation of tm4sf18 in zebrafish delays motile EC selection, generates hypoplastic vessels, sensitizes ECs to fluctuations in pro-angiogenic signal and disrupts angiogenesis. We propose that positive-feedback transforms the normally protracted process of lateral inhibition into a quick, adaptive and robust decision-making mechanism, suggestive of a general framework for temporal modulation of cell fate specification in development and disease.

developmental biology↗