Biology subjects

Bonnet, F.

Publications and source records attributed to Bonnet, F..

8 recordsLinked to original sources

bioRxiv2026

Mesenchymal-derived neural progenitors underlie local insulin production and neuronal transdifferentiation during retina regeneration

In humans, retinal-neuron death, optic-nerve injuries, and associated neurodegenerative diseases, such as glaucoma and age-related macular degeneration, often lead to permanent vision loss. While the capacity for regeneration is low in the human nervous system, including the retina, some non-mammalian vertebrate species, including zebrafish, are capable of endogenous neuronal regeneration after injury. Unlike mammals, zebrafish do not form a scar that inhibits axonal and neuronal regeneration after injury. Rather, they harbor neural progenitor and stem-cell populations allowing regeneration of entire parts of the nervous system and restoration of tissue integrity and function. In the zebrafish retina, cycling neural progenitor cells of the ciliary marginal zone and quiescent resident neural stem cells (the latter of which are also called Muller glial cells) participate in neuronal regeneration following different types of injury. In this study, we report the identification of a novel, additional cellular source participating in neuronal regeneration of neurons in the zebrafish retina after genetic ablation of retinal ganglion cells. Before injury, these progenitor cells express molecular markers of neural-crest-cell and/or fibroblast identity, such as sox10, pdgfrb, and eya2, while after neuronal ablation they also express proneural factors including the ascl1a and olig2 genes. Combining genetic ablation of neurons with photoconversion or Cre/Lox-dependent genetic lineage tracing of sox10-expressing cells, we demonstrated that these cells can differentiate into post-mitotic retinal neurons in the ganglion cell layer (GCL) in the absence of cell proliferation. We also showed, surprisingly, that this progenitor population locally produces insulin mRNA, and that insulin signaling is involved in the accumulation of mesenchymal-derived neural progenitors in the GCL and in their subsequent transdifferentiation into RGCs. This work reveals an unexpected and novel cellular mechanism of transdifferentiation, dependent on a neural-crest-derived mesenchymal cell population, participating in neuronal regeneration in the zebrafish retina. The discovery of this plastic cell population could potentially lead to new strategies to promote the formation of new neurons in the mammalian retina.

developmental biology↗

bioRxiv2026

Injury-induced Cxcl11 and neutrophil signaling drive zebrafish kidney regeneration by generating a nephrogenic niche of Fgf and Wnt expression

Adult zebrafish regenerate their kidneys after injury by activating quiescent renal stem cells, however the injury signals that activate kidney stem cells are not known. We show here that an innate immune, cytokine response after tubule injury is required and sufficient to induce adult zebrafish kidney regeneration. An injury reporter zebrafish transgenic, Tg(kim1:mScarlet3), revealed that tubule injury occurred specifically in kidney proximal tubules and was associated with a rapid accumulation of neutrophils and macrophages. Injury also activated a Tg(NFkB:GFP) reporter transgene specifically in kidney tubules where RNA seq revealed NFkB target gene and cytokine expression. Inhibition of NFkB signaling with JSH-23 blocked Tg(NFkB:GFP) reporter activation and also inhibited induction of new nephrons. Systemic injection of the immune activators lipopolysaccharide or zymosan into uninjured fish rapidly induced cytokine expression followed by nephrogenic gene expression and the appearance of new, functional nephrons. Analysis of injury-induced cytokines revealed that several paralogs of cxcl11 were strongly expressed throughout the regeneration response and injection of recombinant Cxcl11 was sufficient to induce FGF-dependent kidney stem cell aggregation, but not Wnt-dependent epithelial differentiation. Kidney injury in zebrafish expressing a neutrophil dominant negative rac2D57N transgene activated Fgf signaling but failed to induce wnt9b or downstream Wnt target genes. Nephrogenic gene expression and epithelial tubule formation was rescued by treatment with the canonical Wnt agonist CHIR. Our findings demonstrate that an injury-induced, sterile immune response regulates kidney regeneration by establishing a nephrogenic niche of Fgf and Wnt signaling that supports tissue-resident kidney stem cell differentiation into functional nephrons.

developmental biology↗

bioRxiv2025

Multiple Wnt signaling pathways direct epithelial tubule interconnection in the regenerating zebrafish kidney

Epithelial tubule fusion is fundamental for kidney morphogenesis. Differentiating nephron tubules interconnect with collecting system epithelia to generate a lumenal pathway for fluid excretion. In the adult zebrafish kidney, nephrogenesis occurs as a regenerative response to injury and provides a model to explore cell signaling pathways required for tubule interconnection. We show that canonical Wnt signaling at the junction between two tubules induces a mesenchymal, invasive cell phenotype and is required, along with Src kinase and rac1, to generate basal cell protrusions. The Wnt ligands wnt9b and wnt4 are both required for new nephron formation after injury. Mutation in wnt4 or treatment with the canonical Wnt inhibitor IWR1 blocks formation of basal protrusions in forming nephrons. Mutation in the Wnt receptor frizzled9b reveals a fusion-associated non-canonical Wnt pathway that acts to 1) restrict canonical Wnt gene expression, 2) drive Rho kinase-dependent apical constriction of epithelial cells, and 3) position basal protrusions and generate orthogonal tubule lumenal connections. As a result, frizzled9b mutant nephrons fail to fully interconnect with target distal tubules. Our results indicate that canonical and non-canonical Wnt signaling interact in the same cells to orient and drive tubule interconnection in the regenerating zebrafish kidney.

developmental biology↗

bioRxiv2025

Zebrafish genetic model of neuromuscular degeneration associated with Atrogin-1 expression

The degenerative loss of muscle associated with aging leading to muscular atrophy is called sarcopenia. Currently, practicing regular physical exercise is the only efficient way to delay sarcopenia onset. Identification of therapeutic targets to alleviate the symptoms of aging requires in vivo model organisms of accelerated muscle degeneration and atrophy. The zebrafish undergoes aging, with hallmarks including mitochondrial dysfunction, telomere shortening, and accumulation of senescent cells. However, zebrafish age slowly, and no specific zebrafish models of accelerated muscle atrophy associated with molecular events of aging are currently available. We have developed a new genetic tool to efficiently accelerate muscle-fiber degeneration and muscle-tissue atrophy in zebrafish larvae and adults. We used a gain-of-function strategy with a molecule that has been shown to be necessary and sufficient to induce muscle atrophy and a sarcopenia phenotype in mammals: Atrogin-1 (also named Fbxo32). We report the generation, validation, and characterization of a zebrafish genetic model of accelerated neuromuscular atrophy, the atrofish. We demonstrated that Atrogin-1 expression specifically in skeletal muscle tissue induces a muscle atrophic phenotype associated with locomotion dysfunction in both larvae and adult fish. We identified degradation of the myosin light chain as an event occurring prior to muscle-fiber degeneration. Biological processes associated with muscle aging such as proteolysis, inflammation, stress response, extracellular matrix (ECM) remodeling, and apoptosis are upregulated in the atrofish. Surprisingly, we observed a strong correlation between muscle-fiber degeneration and reduced numbers of neuromuscular junctions in the peripheral nervous system, as well as neuronal cell bodies in the spinal cord, suggesting that muscle atrophy could underly a neurodegenerative phenotype in the central nervous system. Finally, while atrofish larvae can recover locomotive functions, adult atrofish have impaired regenerative capacities, as is observed in mammals during muscle aging. In the future, the atrofish could serve as a platform for testing molecules aimed at treating or alleviating the symptoms of muscle aging, thereby opening new therapeutic avenues in the fight against sarcopenia.

developmental biology↗

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↗

bioRxiv2019

Strategies to modulate zebrafish collective dynamics with a closed-loop biomimetic robotic system

The objective of this study is to integrate biomimetic robots into small groups of zebrafish and to modulate their collective behaviours. A possible approach is to have the robots behave like sheepdogs. In this case, the robots would behave like a different species than the fish and would present different relevant behaviours. In this study, we explore different strategies that use biomimetic zebrafish behaviours. In past work, we have shown that robots biomimicking zebrafish can be socially integrated into zebrafish groups. We have also shown that a fish-like robot can modulate the rotation choice of zebrafish groups in a circular set-up. Here, we further study the modulation capabilities of such robots in a more complex set-up. To do this, we exploit zebrafish social behaviours we identified in previous studies. We first modulate collective departure by replicating the leadership mechanisms with the robot in a set-up composed of two rooms connected by a corridor. Then, we test different behavioural strategies to drive the fish groups towards a predefined target room. To drive the biohybrid groups towards a predefined choice, they have to adopt some specific fish-like behaviours. The first strategy is based on a single robot using the initiation behaviour. In this case, the robot keeps trying to initiate a group transition towards the target room. The second strategy is based on two robots, one initiating and one staying in the target room as a social attractant. The third strategy is based on a single robot behaving like a zebrafish but staying in the target room as a social attractant. The fourth strategy uses two robots behaving like zebrafish but staying in the target room. We conclude that robots can modulate zebrafish group behaviour by adopting strategies based on existing fish behaviours. Under these conditions, robots enable the testing of hypotheses about the behaviours of fish.

animal behavior and cognition↗

bioRxiv2019

A data-driven method for reconstructing and modelling social interactions in moving animal groups

Group-living organisms that collectively migrate range from cells and bacteria to human crowds, and include swarms of insects, schools of fish and flocks of birds or ungulates. Unveiling the behavioural and cognitive mechanisms by which these groups coordinate their movements is a challenging task. These mechanisms take place at the individual scale and they can be described as a combination of pairwise interactions between individuals and interactions between these individuals and the physical obstacles in the environment. Thanks to the development of novel tracking techniques that provide large and accurate data sets, the main characteristics of individual and collective behavioural patterns can be quantified with an unprecedented level of precision. However, in a large number of works, social interactions are usually described by force map methods that only have a limited capacity of explanation and prediction, being rarely suitable for a direct implementation in a concise and explicit mathematical model. Here, we present a general method to extract the interactions between individuals that are involved in the coordination of collective movements in groups of organisms. We then apply this method to characterize social interactions in two species of shoaling fish, the rummynose tetra (Hemigrammus rhodostomus) and the zebrafish (Danio rerio), which both present a burst-and-coast motion. The detailed quantitative description of microscopic individual-level interactions thus provides predictive models of the emergent dynamics observed at the macroscopic group-level. This method can be applied to a wide range of biological and social systems.

animal behavior and cognition↗

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↗