Biology subjects

Ribes, V.

Publications and source records attributed to Ribes, V..

5 recordsLinked to original sources

bioRxiv2025

Dual PAX3/7 transcriptional activities spatially encode spinal cell fates through distinct gene networks

Understanding how transcription factors regulate organized cellular diversity in developing tissues remains a major challenge due to their pleiotropic functions. We addressed this by monitoring and genetically modulating the activity of PAX3 and PAX7 during the specification of neural progenitor pools in the embryonic spinal cord. Using mouse models, we show that the balance between the transcriptional activating and repressing functions of these factors is modulated along the dorsoventral axis and is instructive to the patterning of spinal progenitor pools. By combining loss-of-function experiments with functional genomics in spinal organoids, we demonstrate that PAX-mediated repression and activation rely on distinct cis-regulatory genomic modules. This enables both the coexistence of their dual activity in dorsal cell progenitors and the specific control of two major differentiation programs. PAX promotes H3K27me3 deposition at silencers to repress ventral identities, while at enhancers, they act as pioneer factors, opening and activating cis-regulatory modules to specify dorsal-most identities. Finally, we show that this pioneer activity is restricted to cells exposed to BMP morphogens, ensuring spatial specificity. These findings reveal how PAX proteins, modulated by morphogen gradients, orchestrate neuronal diversity in the spinal cord, providing a robust framework for neural subtype specification.

developmental biology↗

bioRxiv2023

Antero-posterior gradients of cell plasticity and proliferation modulate posterior regeneration in the annelid Platynereis

Regenerative abilities are extremely variable among animals and may be substantial in some phyla, such as the annelids. So far, the cellular mechanisms underlying regeneration in annelids remain elusive. To precisely determine the origin(s), plasticity and fate of the cells participating in the blastema formation during posterior regeneration in the annelid Platynereis dumerilii, we developed specific tools to track proliferative cells as well as gut epithelial cells. We showed that two populations of progenitors are at play during regeneration and that, among them, gut progenitors from differentiated tissues are lineage-restricted. Strikingly, gut progenitors from less differentiated and more proliferative tissues are much more plastic and can produce ectodermal and mesodermal derivatives, in addition to gut cells. However, their plasticity is de facto limited as exemplified by their inability to regenerate populations of stem cells responsible for the constant growth of the worms. We evidenced that those stem cells are from local origin (i.e. from the segment abutting the amputation plan) as most of the blastema cells. Our results are in favour of a hybrid and flexible cellular model for posterior regeneration in Platynereis relying on a gradient of cell plasticity along the antero-posterior axis of the animal.

developmental biology↗

bioRxiv2021

Divergent transcriptional and transforming properties of PAX3-FOXO1 and PAX7-FOXO1 paralogs

The hallmarks of the alveolar subclass of rhabdomyosarcoma are chromosomal translocations that generate chimeric PAX3-FOXO1 or PAX7-FOXO1 transcription factors. Both PAX-FOXO1s result in related cell transformation in animal models, but both mutations are associated with distinct pathological manifestations in patients. To assess the mechanisms underlying these differences, we generated isogenic fibroblast lines expressing either PAX-FOXO1 paralog. Mapping of their genomic recruitment using CUT&Tag revealed that the two chimeric proteins have distinct DNA binding preferences. In addition, PAX7-FOXO1 causes stronger de novo transactivation of its bound regions than PAX3-FOXO1, resulting in greater transcriptomic dynamics involving genes regulating cell shape and cycle. Consistently, PAX3-FOXO1 accentuates fibroblast cellular traits associated with contractility and surface adhesion and limits entry into M phase. In contrast, PAX7-FOXO1 drives cells to adopt an amoeboid shape, reduces entry into S phase, and causes more genomic instabilities. Altogether, our results argue that the diversity of rhabdomyosarcoma manifestation arises, in part, from the divergence between the transcriptional activities of PAX3-FOXO1 and PAX7-FOXO1. Furthermore, the identified pronounced deleterious effects of PAX7-FOXO1 provide an explanation for the low frequency of the translocation generating this factor in patients with rhabdomyosarcoma.

cancer biology↗

bioRxiv2020

Dynamic extrinsic pacing of the HOX clock in human axial progenitors controls motor neuron subtype specification

SUMMARYRostro-caudal patterning of vertebrates depends on the temporally progressive activation of HOX genes within axial stem cells that fuel axial embryo elongation. Whether HOX genes sequential activation, the “HOX clock”, is paced by intrinsic chromatin-based timing mechanisms or by temporal changes in extrinsic cues remains unclear. Here, we studied HOX clock pacing in human pluripotent stem cells differentiating into spinal cord motor neuron subtypes which are progenies of axial progenitors. We show that the progressive activation of caudal HOX genes in axial progenitors is controlled by a dynamic increase in FGF signaling. Blocking FGF pathway stalled induction of HOX genes, while precocious increase in FGF alone, or with GDF11 ligand, accelerated the HOX clock. Cells differentiated under accelerated HOX induction generated appropriate posterior motor neuron subtypes found along the human embryonic spinal cord. The HOX clock is thus dynamically paced by exposure parameters to secreted cues. Its manipulation by extrinsic factors alleviates temporal requirements to provide unprecedented synchronized access to human cells of multiple, defined, rostro-caudal identities for basic and translational applications.View Full Text

developmental biology↗

bioRxiv2019

Over-activation of BMP signaling in neural crest cells precipitates heart outflow tract septation

Establishment of separated pulmonary and systemic circulations in vertebrates relies on the key role of neural crest cells (NCC) for the septation of the embryonic cardiac outflow tract (OFT). Absence of NCCs induces OFT septation defects, analogous to a loss of Bone Morphogenetic Proteins (BMPs) activity, though it remains unclear how BMPs control cardiac NCC differentiation and behaviour. To address this question, we monitored cardiac NCC state upon gain in BMP signaling, caused by the deletion of Dullard, using 3D-imaging and single cell transcriptomics. Specific loss of Dullard in the NCC results in premature OFT septation, pulmonary artery obstruction and embryonic death. This is caused by uncontrolled NCC convergence towards the endocardium and asymmetrical myocardial differentiation, promoted by elevated levels of the guiding cue Sema3c and decreased levels in mesenchymal trait markers. Furthermore, we unraveled the molecular basis of the zipper-like OFT septation where graded Sema3c expression follow a gradient of BMP activation in NCC along the OFT length.

developmental biology↗