Biology subjects

Locker, M.

Publications and source records attributed to Locker, M..

4 recordsLinked to original sources

bioRxiv2023

Regeneration from three cellular sources and ectopic mini-retina formation upon neurotoxic retinal degeneration in Xenopus

Regenerative abilities are not evenly distributed across the animal kingdom. Interestingly, the underlying modalities are also highly variable, even among closely related species. In fish or amphibians, retinal repair can involve the mobilization of different cellular sources, including stem cells of the ciliary marginal zone (CMZ), retinal pigmented epithelial (RPE) cells, or Muller glia. The mechanisms that trigger the recruitment of one cell type over another remain elusive. To investigate whether the magnitude of retinal damage might influence the regeneration modality of the Xenopus retina, we developed a model based on cobalt chloride (CoCl2) intraocular injection, allowing for a dose-dependent control of cell death extent. Analyses in Xenopus laevis revealed that limited CoCl2-mediated neurotoxicity only triggers cone cell loss and results in a few Muller glia cells reentering the cell cycle, without affecting CMZ cell activity or recruiting RPE cells. Conversely, we found that severe CoCl2-induced retinal degeneration not only potentializes the proliferative response of Muller cells, but also enhances CMZ cell proliferation and, unexpectedly triggers an RPE reprogramming event. Although Muller glia could not regenerate cones under these conditions, both CMZ and RPE-derived proliferative cells could. Strikingly, RPE reprogrammed cells self-organized into an ectopic layered mini retina-like structure laid on top of the original retina. It is thus likely that the injury paradigm determines the awakening of different stem-like cell populations exhibiting distinct neurogenic capacities. Besides, we surprisingly found that Xenopus tropicalis also has the ability to recruit Muller cells and reprogram its RPE following CoCl2-induced damage, whereas only CMZ cell proliferation was reported in previously examined degenerative models. Altogether, these findings highlight the critical role of the injury paradigm and reveal that three cellular sources can be reactivated in the very same degenerative model.

developmental biology↗

bioRxiv2022

Awakening adult neural stem cells: NOX signalling as a positive regulator of quiescence to proliferation transition in the Xenopus retina

Reactive oxygen species (ROS) are both harmful molecules sustaining the pathogenesis of several diseases and essential modulators of cell behaviours. In particular, a growing wealth of data suggest that ROS-dependent signalling pathways might be critical in conferring embryonic or adult stem cells their specific properties. However, how stem cells control ROS production and scavenging, and how ROS in turn contribute to stemness remain poorly understood. Using the Xenopus retina as a model system, we first investigated the redox status of retinal stem cells (RSCs). We discovered that they exhibit higher ROS levels compared to progenitors and retinal neurons and express a set of specific antioxidant genes. We next addressed the question of ROS functional involvement in these cells. Using pharmacological or genetic tools, we demonstrate that inhibition of NADPH oxidase (NOX)-dependent ROS production increases the proportion of quiescent RSCs. This is surprisingly accompanied by an apparent acceleration of the mean division speed within the remaining proliferating pool. Our data further unveil that such impact on RSC cell cycling is achieved by modulation of the Wnt/Hedgehog signalling balance. Altogether, we highlight that RSCs exhibit distinctive redox characteristics and exploit NOX signalling to limit quiescence and fine-tune their proliferation rate.

developmental biology↗

bioRxiv2022

Late-onset glaucoma in Yap conditional knockout mouse

Glaucoma is an optic neuropathy often referred to as "the silent thief of sight", due to its late diagnosis, which is generally made when degeneration of the optic nerve and retinal ganglion cells is already well under way. It is thus of utmost importance to have a better understanding of the disease, and to investigate more deeply the early causes of glaucoma. The transcriptional coactivator YAP recently emerged as an important regulator of eye homeostasis and is drawing attention in the glaucoma research field. Here we show that Yap conditional knockout mice (Yap cKO), in which the deletion of Yap is induced in both Muller glia (i.e. the only retinal YAP-expressing cells) and the non-pigmented epithelial cells of the ciliary body, exhibit breakdown of the aqueous-blood barrier accompanied by progressive collapse of the ciliary body as we observed in human uveitic patients. In addition, aged Yap cKO mice harbor glaucoma features, including alteration of glutamate recycling, deregulation of key homeostatic Muller-derived proteins, retinal vascular defects, optic nerve degeneration, and retinal ganglion cell death. Together, our findings reveal the essential role of YAP in preserving the ciliary body and the retinal ganglion cells, thereby preventing the onset of glaucoma features.

neuroscience↗

bioRxiv2018

Linking YAP to Müller glia quiescence exit in the degenerative retina

Contrasting with fish or amphibian, retinal regeneration from Muller glial cells is largely limited in mammals. In our quest towards the identification of molecular cues that may boost their stemness potential, we investigated the involvement of the Hippo pathway effector YAP, which we previously found to be upregulated in Muller cells following retinal injury. We report that conditional Yap deletion in Muller cells prevents the upregulation of cell cycle genes that normally accompanies reactive gliosis upon photoreceptor cell death. This occurs as a consequence of defective EGFR signaling. Consistent with a function of YAP in triggering Muller glia cell cycle re-entry, we further show that in Xenopus, a species endowed with efficient regenerative capacity, YAP is required for their injury-dependent proliferative response. Finally, and noteworthy, we reveal that YAP overactivation in mouse Muller cells is sufficient to induce their reprogramming into highly proliferative cells. Overall, we unravel a pivotal role for YAP in tuning Muller cell response to injury and highlight a novel YAP-EGFR axis by which Muller cells exit their quiescence state, a critical step towards regeneration.

developmental biology↗