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 Müller glia. We first discovered an unexpected temporal dynamic of gene compensation. At postnatal stages, Taz upregulation occurs, leading to a gain of function-like phenotype characterised 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 Müller 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 Müller cell-specific conditional Yap-knockout aged mice. Together, this study highlights a novel YAP function in Müller 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.

Müller glial cell-dependent regeneration of the neural retina: An overview across vertebrate model systems.

Retinal dystrophies are a major cause of blindness for which there are currently no curative treatments. Transplantation of stem cell-derived neuronal progenitors to replace lost cells has been widely investigated as a therapeutic option. Another promising strategy would be to trigger self-repair mechanisms in patients, through the recruitment of endogenous cells with stemness properties. Accumulating evidence in the past 15 year0s has revealed that several retinal cell types possess neurogenic potential, thus opening new avenues for regenerative medicine. Among them, Müller glial cells have been shown to be able to undergo a reprogramming process to re-acquire a stem/progenitor state, allowing them to proliferate and generate new neurons for repair following retinal damages. Although Müller cell-dependent spontaneous regeneration is remarkable in some species such as the fish, it is extremely limited and ineffective in mammals. Understanding the cellular events and molecular mechanisms underlying Müller cell activities in species endowed with regenerative capacities could provide knowledge to unlock the restricted potential of their mammalian counterparts. In this context, the present review provides an overview of Müller cell responses to injury across vertebrate model systems and summarizes recent advances in this rapidly evolving field. Developmental Dynamics 245:727-738, 2016. © 2015 The Authors. Developmental Dynamics published by Wiley Periodicals, Inc.

Stemness or not stemness? Current status and perspectives of adult retinal stem cells.

Many retinal dystrophies are associated with photoreceptor loss, which causes irreversible blindness. The recent identification of various sources of stem cells in the mammalian retina has raised the possibility that cell-based therapies might be efficient strategies to treat a wide range of incurable eye diseases. A first step towards the successful therapeutic exploitation of these cells is to unravel intrinsic and extrinsic regulators that control their proliferation and cell lineage determination. In this review, we provide an overview of the different types and molecular fingerprints of retinal stem cells identified so far. We also detail the current knowledge on molecular cues that influence their self-renewal and proliferation capacity. In particular, we focus on recent data implicating developmental signaling pathways, such as Wnt, Notch and Hedeghog, both in the normal and regenerating retina in different animal models. Last, we discuss the potential of ES cells and various adult stem cells for retinal repair.

A general role of hedgehog in the regulation of proliferation.

The Hedgehog (Hh) pathway regulates proliferation in a variety of tissues, however its specific effects on the cell cycle are unclear. During retinal proliferation in particular, the role of Hh has been controversial, with studies variably suggesting a stimulatory or an inhibitory effect on proliferation. Our recent data provide an underlying mechanism, which reconciles these different views. We showed that Hh signaling in the retina accelerates the G(1) and G(2) phases of the cell cycle and then pushes these rapidly dividing cells out of the cell cycle prematurely. From this and other evidence, we propose that Hh converts quiescent retinal stem cells into fast-cycling transient amplifying progenitors that are closer to cell cycle exit and differentiation. This is, we suggest, likely to be a general role of Hh in the nervous system and other tissues. This function of Hh in cell cycle kinetics and cell cycle exit may have implications for tumorigenesis and brain evolution.

Comparison of the expression patterns of five neural RNA binding proteins in the Xenopus retina.

An increasing body of evidence indicates that gene expression can be modulated by posttranscriptional mechanisms. RNA binding proteins, for instance, control gene expression at many regulatory levels including RNA splicing, transport, stability, and translation. Although numerous RNA binding proteins have been identified, very few have been studied extensively in the context of developmental processes. We focused our study on five neural RNA binding proteins: one Musashi homolog, Nrp-1, one member of the Bruno gene family, BruL-1 (also known as Etr-1), and three members of the ELAV/Hu family, ElrB, ElrC, and ElrD. As an initial step in addressing their function during Xenopus neurogenesis, we used in situ hybridization to determine their expression patterns during retinal development. We found that RNA binding proteins belonging to different families have distinct spatio-temporal expression. These combinatorial expression patterns are reminiscent of previously described cell type-specific expression patterns of transcription factors during retinal development. The distribution of RNA binding proteins within the retina suggests that these regulators of posttranscriptional events may play important roles in multiple steps of retinogenesis.

Retinal stem cells in vertebrates: parallels and divergences.

During the development of the nervous system, after a given number of divisions, progenitors exit the cell cycle and differentiate as neurons or glial cells. Some cells however do not obey this general rule and persist in a progenitor state. These cells, called stem cells, have the ability to self-renew and to generate different lineages. Understanding the mechanisms that allow stem cells to "resist" differentiating stimuli is currently one of the most fascinating research areas for biologists. The amphibian and fish retinas, known to contain stem cell populations, have been pioneering models for neural stem cell research. The Xenopus retina enabled the characterization of the genetic processes that occur in the path from a pluripotent stem cell to a committed progenitor to a differentiated neuron. More recently, the discovery that avian and mammalian retinas also contain stem cell populations, has contributed to the definitive view of the adult nervous system of upper vertebrates as a more dynamic and plastic structure than previously thought. This has attracted the attention of clinicians who are attempting to employ stem cells for transplantation into damaged tissue. Research in this area is promising and will represent a key instrument in the fight against blindness and retinal dystrophies. In this review, we will focus primarily on describing the main characteristics of various retinal stem cell populations, highlighting their divergences during evolution, and their potential for retinal cell transplantation. We will also give an overview of the signaling cascades that could modulate their potential and plasticity.