Biology subjects

Roger, J. E.

Publications and source records attributed to Roger, J. E..

6 recordsLinked to original sources

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↗

bioRxiv2021

A non-transcriptional function of Yap orchestrates the DNA replication program

In multicellular eukaryotic organisms, the initiation of DNA replication occurs asynchronously throughout S-phase according to a regulated replication timing program. Here, using Xenopus egg extracts, we showed that Yap (Yes-associated protein 1), a downstream effector of the Hippo signaling pathway, is required for the control of DNA replication dynamics. We found that Yap is recruited to chromatin at the start of DNA replication and that Yap depletion accelerates DNA replication dynamics by increasing the number of activated replication origins. Furthermore, we identified Rif1, a major regulator of the DNA replication timing program, as a novel Yap binding protein. In Xenopus embryos, using a Trim-Away approach during cleavage stages devoid of transcription, we found that both Yap and Rif1 depletion trigger an acceleration of cell divisions, suggesting a shorter S-phase by alterations of the replication program. Finally, our data show that Rif1 knockdown leads to defects in the partitioning of early versus late replication foci in retinal stem cells, as we previously showed for Yap. Altogether, our findings unveil a non-transcriptional role for Yap in regulating replication dynamics. We propose that Yap and Rif1 function as breaks to control the DNA replication program in early embryos and post-embryonic stem cells. HighlightsO_LIYap is recruited to chromatin during DNA replication dependent on pre-replicative complex assembly. C_LIO_LIYap controls DNA replication dynamics by limiting origin firing. C_LIO_LIThe replication timing regulatory factor 1, Rif1, is a novel Yap binding-partner. C_LIO_LIBoth Yap and Rif1 regulate the length of the first embryonic cell cycles. C_LIO_LILike Yap, Rif1 controls retinal stem cell DNA replication timing. C_LI

developmental biology↗

bioRxiv2021

Glycogen Synthase Kinase 3 regulates the genesis of the rare displaced ganglion cell retinal subtype

Glycogen Synthase Kinase 3 (GSK) proteins (GSK3 and GSK3{beta}) are key mediators of signaling pathways, with crucial roles in coordinating fundamental biological processes during neural development. Here we show that the complete loss of GSK3 signaling in mouse retinal progenitors leads to microphthalmia with broad morphological defects. Both proliferation of retinal progenitors and neuronal differentiation are impaired and result in enhanced cell death. A single wild-type allele of either Gsk3 or Gsk3{beta} is able to rescue these phenotypes. In this genetic context, all cell types are present with a functional retina. However, we unexpectedly detect a large number of cells in the inner nuclear layer expressing retinal ganglion cell (RGC)-specific markers (called displaced RGCs, dRGCs) when at least one allele of Gsk3 is expressed. Excess dRGCs lead to increased number of axons projecting into the ipsilateral medial terminal nucleus, an area of the brain belonging to the non-image-forming visual circuit and poorly targeted by RGCs in wild-type retina. Transcriptome analysis and optomotor response assay suggest that at least a subset of dRGCs in Gsk3 mutant mice are direction-selective RGCs. Our study thus uncovers a unique role of GSK3 in controlling the genesis of dRGCs, a rare and poorly characterized retinal cell type.

neuroscience↗

bioRxiv2020

AMP-activated-kinase (AMPK) is essential sensor and metabolic regulator of retinal neurons and their integrated metabolism with RPE.

The retina has one of the highest energy demands in the human body, and proper regulation of metabolism among the cell types of the retina is required for functional vision. Recent studies have reported that retinal metabolism is disrupted during retinal degeneration and aging, while therapies designed to enhance metabolism can slow or prevent degeneration. Here, we show that multiple metabolic pathways, including those regulated by a key ATP sensor and regulator of metabolism, AMP-activated-kinase (AMPK), were dysregulated in a model of inherited retinal degeneration. In order to assess the direct role of AMPK in regulating retinal metabolism, we used mice with retina-specific knockout of AMPK activity. Conditional loss of AMPK resulted in impaired visual function at an early age, with slow photoreceptor loss observed in older mice. Moreover, we found that loss of AMPK resulted in decreased metabolic flux from glucose, decreased mitochondrial DNA copy number, decreased mitochondrial-related gene expression, and alterations in mitochondrial morphology in the photoreceptors, all of which preceded degeneration. Surprisingly, metabolic changes from the loss of AMPK in retinal neurons also resulted in secondary degeneration of retinal pigment epithelial (RPE) cells. Together, these data show that AMPK signaling is important for maintaining metabolic homeostasis of the retina and support the hypothesis that photoreceptors and RPE have a shared metabolic ecosystem that is controlled, in part, by AMPK.

neuroscience↗

bioRxiv2020

Yap haploinsufficiency leads to Müller cell dysfunction and late-onset cone dystrophy

Hippo signalling regulates eye growth during embryogenesis through its effectors YAP and TAZ. Taking advantage of a Yap heterozygous mouse line, we here sought to examine its function in adult neural retina, where YAP expression is restricted to Muller glia. We first discovered an unexpected temporal dynamic of gene compensation. At post-natal stages, Taz upregulation occurs, leading to a gain of function-like phenotype characterized by EGFR signalling potentiation and delayed cell cycle exit of retinal progenitors. In contrast, Yap+/- adult retinas no longer exhibit TAZ-dependent dosage compensation. In this context, Yap haploinsufficiency in aged individuals results in Muller glia dysfunction, late-onset cone degeneration and reduced cone-mediated visual response. Alteration of glial homeostasis and altered patterns of cone opsins were also observed in Muller cell specific conditional Yap knockout mice. Together, this study highlights a novel YAP function in Muller cells for the maintenance of retinal tissue homeostasis and the preservation of cone integrity. It also suggests that YAP haploinsufficiency should be considered and explored as a cause of cone dystrophies in human. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=101 SRC="FIGDIR/small/953943v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@166de41org.highwire.dtl.DTLVardef@898b74org.highwire.dtl.DTLVardef@22ad92org.highwire.dtl.DTLVardef@b189dc_HPS_FORMAT_FIGEXP M_FIG C_FIG Main Points O_LIThis study finds unsuspected dynamics of YAP compensatory mechanisms in the retina of Yap+/- mice C_LIO_LIYap haploinsufficiency results in Muller glia dysfunction in aged mice, leading to late-onset cone dystrophy C_LI

neuroscience↗

bioRxiv2019

HDAC inhibition ameliorates cone survival in retinitis pigmentosa mice

Cone photoreceptor cell death in inherited retinal diseases, such as Retinitis Pigmentosa (RP), leads to the loss of high acuity and color vision and ultimately to blindness. In RP, a vast number of mutations perturb the structure and function of rod photoreceptors while cones remain initially unaffected. Cone death follows rod death secondarily due to increased oxidative stress, inflammation, and loss of structural and nutritional support provided by rods. Here, we show that secondary cone cell death in animal models for RP was associated with an increased activity of histone deacetylates (HDACs). A single intravitreal injection of an HDAC inhibitor at a late stage of the disease, when majority of rods have already degenerated, was sufficient to delay cone death and support long-term cone survival. Moreover, the surviving cones remained light sensitive and initiated light-driven ganglion cell responses. RNA-seq analysis of protected cones demonstrated that HDAC inhibition led to multi-level protection via regulation of different pro-survival pathways, including MAPK, PI3K-Akt, and autophagy. This study suggests a unique possibility for a targeted pharmacological protection of both primary degenerating rods and secondary dying cones by HDAC inhibition and creates hope to maintain vision in RP patients independent of the disease stage.

neuroscience↗