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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 Müller 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 theXenopusretina, we developed a model based on cobalt chloride (CoCl2) intraocular injection, allowing for a dose-dependent control of cell death extent. Analyses inXenopus laevisrevealed that limited CoCl2-mediated neurotoxicity only triggers cone cell loss and results in a few Müller 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 Müller cells, but also enhances CMZ cell proliferation and, unexpectedly triggers an RPE reprogramming event. Although Müller 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 thatXenopus tropicalisalso has the ability to recruit Müller 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.

A hallmark of Wnt/β-Catenin signaling is the extreme diversity of its transcriptional response, which varies depending on the cell and developmental context. What controls this diversity is poorly understood. In all cases, the switch from transcriptional repression to activation depends on a nuclear increase in β-Catenin, which detaches the transcription factor T cell factor 7 like 1 (Tcf7l1) bound to Groucho (Gro) transcriptional co-repressors from its DNA-binding sites and transiently converts Tcf7/Lymphoid enhancer binding factor 1 (Lef1) into a transcriptional activator. One of the earliest and evolutionarily conserved functions of Wnt/β-Catenin signaling is the induction of the blastopore lip organizer. Here, we demonstrate that the evolutionarily conserved BarH-like homeobox-2 (Barhl2) protein stabilizes the Tcf7l1-Gro complex and maintains the repressed expression of Tcf target genes by a mechanism that depends on histone deacetylase 1 (Hdac-1) activity. In this way, Barhl2 switches off the Wnt/β-Catenin-dependent early transcriptional response, thereby limiting the formation of the organizer in time and/or space. This study reveals a novel nuclear inhibitory mechanism of Wnt/Tcf signaling that switches off organizer fate determination., L'une des caractéristiques de la signalisation de Wnt/β-Catenin est l'extrême diversité de sa réponse transcriptionnelle, qui varie en fonction de la cellule et du contexte de développement. Ce qui contrôle cette diversité est mal compris. Dans tous les cas, le passage de la répression transcriptionnelle à l'activation dépend d'une augmentation nucléaire de la β-Caténine, qui détache le facteur de transcription T (Tcf7l1) lié aux co-répresseurs transcriptionnels de Groucho (Gro) de ses sites de liaison ADN et transforme temporairement Tcf7 en un activateur de la transcription. L'une des premières fonctions de signalisation de Wnt/β-Catenin, conservée au cours de l'évolution, est l'induction de l'organiseur de lSpemann. Nous démontrons ici que la protéine BarH-like Homeobox-2 (Barhl2), conservée au cours de l'évolution, stabilise le complexe Tcf7l1-Gro et maintient l'expression réprimée des gènes cibles du Tcf par un mécanisme qui dépend de l'activité des histone désacétylases 1 (Hdac-1). De cette façon, Barhl2 désactive la réponse transcriptionnelle précoce dépendante de Wnt/β-Catenin, limitant ainsi la formation de l'organisateur dans le temps et/ou l'espace. Cette étude révèle un nouveau mécanisme d'inhibition nucléaire de la signalisation Wnt/Tcf qui désactive la détermination du sort de l'organisateur.

Background: Amacrine interneurons that modulate synaptic plasticity between bipolar and ganglion cells constitute the most diverse cell type in the retina. Most are inhibitory neurons using either GABA or glycine as neurotransmitters. Although several transcription factors involved in amacrine cell fate determination have been identified, mechanisms underlying amacrine cell subtype specification remain to be further understood. The Prdm13 histone methyltransferase encoding gene is a target of the transcription factor Ptf1a, an essential regulator of inhibitory neuron cell fate in the retina. Here, we have deepened our knowledge on its interaction with Ptf1a and investigated its role in amacrine cell subtype determination in the developing Xenopus retina. Methods: We performed prdm13 gain and loss of function in Xenopus and assessed the impact on retinal cell fate determination using RT-qPCR, in situ hybridization and immunohistochemistry. Results: We found that prdm13 in the amphibian Xenopus is expressed in late retinal progenitors and in about half of the mature amacrine cells, predominantly in glycinergic ones. Clonal analysis in the retina reveals that prdm13 overexpression favours amacrine cell fate determination, with a bias towards glycinergic cells. Conversely, knockdown of prdm13 specifically inhibits glycinergic amacrine cell genesis. We also showed that, as in the neural tube, prdm13 is subjected to a negative autoregulation in the retina. Our data suggest that this is likely due to its ability to repress the expression of its inducer, ptf1a. Conclusions: Our results demonstrate that Prdm13, downstream of Ptf1a, acts as an important regulator of glycinergic amacrine subtype specification in the Xenopus retina. We also reveal that Prdm13 regulates ptf1a expression through a negative feedback loop., SCOPUS: ar.j, info:eu-repo/semantics/published

International audience

Background: In recent years, considerable knowledge has been gained on the molecular mechanisms underlying retinal cell fate specification. However, hitherto studies focused primarily on the six major retinal cell classes (five types of neurons of one type of glial cell), and paid little attention to the specification of different neuronal subtypes within the same cell class. In particular, the molecular machinery governing the specification of the two most abundant neurotransmitter phenotypes in the retina, GABAergic and glutamatergic, is largely unknown. In the spinal cord and cerebellum, the transcription factor Ptf1a is essential for GABAergic neuron production. In the mouse retina, Ptf1a has been shown to be involved in horizontal and most amacrine neurons differentiation.Results: In this study, we examined the distribution of neurotransmitter subtypes following Ptf1a gain and loss of function in the Xenopus retina. We found cell-autonomous dramatic switches between GABAergic and glutamatergic neuron production, concomitant with profound defects in the genesis of amacrine and horizontal cells, which are mainly GABAergic. Therefore, we investigated whether Ptf1a promotes the fate of these two cell types or acts directly as a GABAergic subtype determination factor. In ectodermal explant assays ... Conclusion: Altogether, our results reveal for the first time in the retina a major player in the GABAergic versus glutamatergic cell specification genetic pathway. peerReviewed

BACKGROUND AND PURPOSE: Although the subthalamic nucleus is the most frequently used target for surgical treatment of Parkinson’s disease, the criteria on which it can be identified on T2-weighted images have never been clearly defined. This study was conducted to characterize the precise anatomic distribution of T2-weighted hyposignal in the subthalamic region and to correlate this hyposignal with iron content in the subthalamic nucleus. METHODS: The T2-weighted MR imaging acquisitions of 15 patients with Parkinson’s disease were fused with a digitized version of the Schaltenbrand and Wahren anatomic atlas. The MR signal intensity within the anatomic limits of the subthalamic nucleus was evaluated. An anatomic specimen obtained at autopsy was used to evaluate iron content. RESULTS: In all patients, the subthalamic nucleus was hypointense on both sides in the anterior half of the nucleus. At more posterior levels of the nucleus, hypointensity was less frequently observed (20–80%). Hypointensity was never observed at the most posterior pole. Iron was present in the anteromedial part of the nucleus but absent at the most posterior levels. CONCLUSION: The hypointense signal intensity located lateral to the red nucleus and dorsolateral to the substantia nigra correlates with the presence of iron and corresponds anatomically to the subthalamic nucleus. It can therefore be used as a landmark for electrode implantation in patients with Parkinson’s disease. It should, however, be emphasized that although hypointensity was always present in the anterior half of the subthalamic nucleus, the posterior part of the nucleus was not visible in most cases.

International audience; no abstract

International audience; no abstract

International audience; This anatomic study presents an analysis of the distribution of calbindin immunohistochemistry in the human striatopallidal complex. Entire brains were sectioned perpendicularly to the mid-commissural line into 70-microm-thick sections. Every tenth section was immunostained for calbindin. Calbindin labeling exhibited a gradient on the basis of which three different regions were defined: poorly labeled, strongly labeled, and intermediate. Corresponding contours were traced in individual sections and reformatted as three-dimensional structures. The poorly labeled region corresponded to the dorsal part of the striatum and to the central part of the pallidum. The strongly labeled region included the ventral part of the striatum, the subcommissural part of the external pallidum but also the adjacent portion of its suscommissural part, and the anterior pole of the internal pallidum. The intermediate region was located between the poorly and strongly labeled regions. As axonal tracing and immunohistochemical studies in monkeys show a similar pattern, poorly, intermediate, and strongly labeled regions were considered as the sensorimotor, associative, and limbic territories of the human striatopallidal complex, respectively. However, the boundaries between these territories were not sharp but formed gradients of labeling, which suggests overlapping between adjacent territories. Similarly, the ventral boundary of the striatopallidal complex was blurred, suggesting a structural intermingling with the substantia innominata. This three-dimensional partitioning of the human striatopallidal complex could help to define functional targets for high-frequency stimulation with greater accuracy and help to identify new stimulation sites.