Hippo‐yap signaling in ocular development and disease

Lee, Matthew; Goraya, Navneet; Kim, Seonhee; Cho, Seo‐Hee

doi:10.1002/dvdy.24628

Cited by 41 publications

(26 citation statements)

References 130 publications

(216 reference statements)

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“…SC1 and SC2 were enriched for genes that exhibited monotonic decreases in expression during development. SC1 was enriched for genes associated with signaling pathways (e.g., Wnt, Hippo) implicated in proliferation and lineage commitment (Aldiri et al., 2013, Lee et al., 2018, Liu et al., 2003), whereas SC2 contained cell-cycle genes that are suppressed when cell proliferation nears completion. SC3 was enriched for synapse genes showing increased expression starting at E12/E14 (inner retina differentiation), whereas higher expression of SC4 genes was observed postnatally (phototransduction, ligand receptors).…”

Section: Resultsmentioning

confidence: 99%

Improved Retinal Organoid Differentiation by Modulating Signaling Pathways Revealed by Comparative Transcriptome Analyses with Development In Vivo

et al. 2019

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Stem cell-derived retinal organoids recapitulate many landmarks of in vivo differentiation but lack functional maturation of distinct cell types, especially photoreceptors. Using comprehensive temporal transcriptome analyses, we show that transcriptome shift from postnatal day 6 (P6) to P10, associated with morphogenesis and synapse formation during mouse retina development, was not evident in organoids, and co-expression clusters with similar patterns included different sets of genes. Furthermore, network analysis identified divergent regulatory dynamics between developing retina in vivo and in organoids, with temporal dysregulation of specific signaling pathways and delayed or reduced expression of genes involved in photoreceptor function(s) and survival. Accordingly, addition of docosahexaenoic acid and fibroblast growth factor 1 to organoid cultures specifically promoted the maturation of photoreceptors, including cones. Our study thus identifies regulatory signals deficient in developing retinal organoids and provides experimental validation by producing a more mature retina in vitro, thereby facilitating investigations in disease modeling and therapies.

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Section: Resultsmentioning

confidence: 99%

Improved Retinal Organoid Differentiation by Modulating Signaling Pathways Revealed by Comparative Transcriptome Analyses with Development In Vivo

et al. 2019

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“…Nf2 loss of function in RPCs leads to their expansion through persistent cell cycle progression, albeit at a slow rate (73). Importantly, Nf2 function in RPCs is mediated by YAP/TAZ transcriptional coregulators, which in the absence of Nf2 translocate to the nucleus and mediate transcription of multiple target genes (42,(73)(74)(75). Consistent with this, loss of YAP function in the retina leads to accelerated RPC cell cycle progression (76), further supporting a hypothesis that increase in YAP/TAZ activity due to partial loss of Nf2 function may explain persistent slow proliferation of low choline RPCs.…”

Section: Discussionmentioning

confidence: 99%

Low availability of choline in utero disrupts development and function of the retina

et al. 2019

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Adequate supply of choline, an essential nutrient, is necessary to support proper brain development. Whether prenatal choline availability plays a role in development of the visual system is currently unknown. In this study, we addressed the role of in utero choline supply for the development and later function of the retina in a mouse model. We lowered choline availability in the maternal diet during pregnancy and assessed proliferative and differentiation properties of retinal progenitor cells (RPCs) in the developing prenatal retina, as well as visual function in adult offspring. We report that low choline availability during retinogenesis leads to persistent retinal cytoarchitectural defects, ranging from focal lesions with displacement of retinal neurons into subretinal space to severe hypocellularity and ultrastructural defects in photoreceptor organization. We further show that low choline availability impairs timely differentiation of retinal neuronal cells, such that the densities of early‐born retinal ganglion cells, amacrine and horizontal cells, as well as cone photoreceptor precursors, are reduced in low choline embryonic d 17.5 retinas. Maintenance of higher proportions of RPCs that fail to exit the cell cycle underlies aberrant neuronal differentiation in low choline embryos. Increased RPC cell cycle length, and associated reduction in neurofibromin 2/Merlin protein, an upstream regulator of the Hippo signaling pathway, at least in part, explain aberrant neurogenesis in low choline retinas. Furthermore, we find that animals exposed to low choline diet in utero exhibit a significant degree of intraindividual variation in vision, characterized by marked functional discrepancy between the 2 eyes in individual animals. Together, our findings demonstrate, for the first time, that choline availability plays an essential role in the regulation of temporal progression of retinogenesis and provide evidence for the importance of adequate supply of choline for proper development of the visual system.—Trujillo‐Gonzalez, I., Friday, W. B., Munson, C. A., Bachleda, A., Weiss, E. R., Alam, N. M., Sha, W., Zeisel, S. H., Surzenko, N. Low availability of choline in utero disrupts development and function of the retina. FASEB J. 33, 9194–9209 (2019). http://www.fasebj.org

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“…Studying developmental signalling pathways can thus allow the identification of possible causes of retinal disorders in adults, pinpointing possible targets for therapeutic approaches. The Hippo signalling tightly regulates eye development, and its deregulation in animal models leads to severe ocular defects (reviewed in 3 , 4 ). This signalling pathway consists of a kinase cascade that ultimately phosphorylates the transcription coactivators YAP (Yes associated protein) and TAZ (WW domain-containing transcription regulator 1), causing their retention in the cytoplasm or their degradation.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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 TAZdependent 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.

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Hippo‐yap signaling in ocular development and disease

Cited by 41 publications

References 130 publications

Improved Retinal Organoid Differentiation by Modulating Signaling Pathways Revealed by Comparative Transcriptome Analyses with Development In Vivo

Improved Retinal Organoid Differentiation by Modulating Signaling Pathways Revealed by Comparative Transcriptome Analyses with Development In Vivo

Low availability of choline in utero disrupts development and function of the retina

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

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