The Hippo pathway effector Yki downregulates Wg signaling to promote retinal differentiation in the <i>Drosophila</i> eye

Wittkorn, Erika Lynn; Sarkar, Ankita; Garcia, Kristine; Kango‐Singh, Madhuri; Singh, Amit

doi:10.1242/dev.117358

Cited by 35 publications

(28 citation statements)

References 129 publications

(170 reference statements)

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“…Adult flies were prepared for imaging by freezing at −20 °C for approximately 2 hours followed by mounting the fly on a dissection needle 54 , 86 . The needle with the fly was aligned horizontally over a glass slide using molding putty.…”

Section: Methodsmentioning

confidence: 99%

A soy protein Lunasin can ameliorate amyloid-beta 42 mediated neurodegeneration in Drosophila eye

Sarkar

Gogia

Glenn

et al. 2018

Sci Rep

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Alzheimer’s disease (AD), a fatal progressive neurodegenerative disorder, also results from accumulation of amyloid-beta 42 (Aβ42) plaques. These Aβ42 plaques trigger oxidative stress, abnormal signaling, which results in neuronal death by unknown mechanism(s). We misexpress high levels of human Aβ42 in the differentiating retinal neurons of the Drosophila eye, which results in the Alzheimer’s like neuropathology. Using our transgenic model, we tested a soy-derived protein Lunasin (Lun) for a possible role in rescuing neurodegeneration in retinal neurons. Lunasin is known to have anti-cancer effect and reduces stress and inflammation. We show that misexpression of Lunasin by transgenic approach can rescue Aβ42 mediated neurodegeneration by blocking cell death in retinal neurons, and results in restoration of axonal targeting from retina to brain. Misexpression of Lunasin downregulates the highly conserved cJun-N-terminal Kinase (JNK) signaling pathway. Activation of JNK signaling can prevent neuroprotective role of Lunasin in Aβ42 mediated neurodegeneration. This neuroprotective function of Lunasin is not dependent on retinal determination gene cascade in the Drosophila eye, and is independent of Wingless (Wg) and Decapentaplegic (Dpp) signaling pathways. Furthermore, Lunasin can significantly reduce mortality rate caused by misexpression of human Aβ42 in flies. Our studies identified the novel neuroprotective role of Lunasin peptide, a potential therapeutic agent that can ameliorate Aβ42 mediated neurodegeneration by downregulating JNK signaling.

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Section: Methodsmentioning

confidence: 99%

A soy protein Lunasin can ameliorate amyloid-beta 42 mediated neurodegeneration in Drosophila eye

Sarkar

Gogia

Glenn

et al. 2018

Sci Rep

Self Cite

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“…Wild-type and constitutively active Yki expression in proliferating cells of the eye with eygal4 or constitutively with Actgal4 resulted in loss of eye structures ( S4U-S4V’ Fig ) reminiscent of ex loss [ 55 – 56 ] and as seen with Yki expression limited to the dorsal-ventral margins with bigal4 [ 57 ]. As with loss of ex , the block in differentiation from Yki over-expression with eygal4 in our study or bigal4 [ 57 ] was suppressed by loss of wingless ( wg ) so likely resulted from effects of increased wg blocking progression of the Morphogenetic Furrow (MF). All together, the organ size phenotypes of Rae1 loss-of-function or over-expression are consistent with a role for Rae1 to promote organ size and are consistent with Rae1 inhibition by the Hippo Pathway ( Fig 1 and S2 Fig ) to restrict organ size.…”

Section: Resultsmentioning

confidence: 99%

The Hippo Pathway Targets Rae1 to Regulate Mitosis and Organ Size and to Feed Back to Regulate Upstream Components Merlin, Hippo, and Warts

et al. 2016

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Hippo signaling acts as a master regulatory pathway controlling growth, proliferation, and apoptosis and also ensures that variations in proliferation do not alter organ size. How the pathway coordinates restricting proliferation with organ size control remains a major unanswered question. Here we identify Rae1 as a highly-conserved target of the Hippo Pathway integrating proliferation and organ size. Genetic and biochemical studies in Drosophila cells and tissues and in mammalian cells indicate that Hippo signaling promotes Rae1 degradation downstream of Warts/Lats. In proliferating cells, Rae1 loss restricts cyclin B levels and organ size while Rae1 over-expression increases cyclin B levels and organ size, similar to Hippo Pathway over-activation or loss-of-function, respectively. Importantly, Rae1 regulation by the Hippo Pathway is crucial for its regulation of cyclin B and organ size; reducing Rae1 blocks cyclin B accumulation and suppresses overgrowth caused by Hippo Pathway loss. Surprisingly, in addition to suppressing overgrowth, reducing Rae1 also compromises survival of epithelial tissue overgrowing due to loss of Hippo signaling leading to a tissue “synthetic lethality” phenotype. Excitingly, Rae1 plays a highly conserved role to reduce the levels and activity of the Yki/YAP oncogene. Rae1 increases activation of the core kinases Hippo and Warts and plays a post-transcriptional role to increase the protein levels of the Merlin, Hippo, and Warts components of the pathway; therefore, in addition to Rae1 coordinating organ size regulation with proliferative control, we propose that Rae1 also acts in a feedback circuit to regulate pathway homeostasis.

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“…Similarly, one pathway, HIPPO signaling, was activated in both of the RCS samples as compared to LE but was inhibited in RCS hNPCs compared to RCS (Figure D). HIPPO signaling regulates cell survival, retinogenesis, and photoreceptor cell differentiation . Feasibly, numerous hNPC‐induced signaling mechanisms may be interacting and working in concert with each other to aid in photoreceptor survival and neuroprotection.…”

Section: Discussionmentioning

confidence: 99%

In Vitro and In Vivo Proteomic Comparison of Human Neural Progenitor Cell‐Induced Photoreceptor Survival

et al. 2019

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Retinal degenerative diseases lead to blindness with few treatments. Various cell‐based therapies are aimed to slow the progression of vision loss by preserving light‐sensing photoreceptor cells. A subretinal injection of human neural progenitor cells (hNPCs) into the Royal College of Surgeons (RCS) rat model of retinal degeneration has aided in photoreceptor survival, though the mechanisms are mainly unknown. Identifying the retinal proteomic changes that occur following hNPC treatment leads to better understanding of neuroprotection. To mimic the retinal environment following hNPC injection, a co‐culture system of retinas and hNPCs is developed. Less cell death occurs in RCS retinal tissue co‐cultured with hNPCs than in retinas cultured alone, suggesting that hNPCs provide retinal protection in vitro. Comparison of ex vivo and in vivo retinas identifies nuclear factor (erythroid‐derived 2)‐like 2 (NRF2) mediated oxidative response signaling as an hNPC‐induced pathway. This is the first study to compare proteomic changes following treatment with hNPCs in both an ex vivo and in vivo environment, further allowing the use of ex vivo modeling for mechanisms of retinal preservation. Elucidation of the protein changes in the retina following hNPC treatment may lead to the discovery of mechanisms of photoreceptor survival and its therapeutic for clinical applications.

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The Hippo pathway effector Yki downregulates Wg signaling to promote retinal differentiation in the Drosophila eye

Cited by 35 publications

References 129 publications

A soy protein Lunasin can ameliorate amyloid-beta 42 mediated neurodegeneration in Drosophila eye

A soy protein Lunasin can ameliorate amyloid-beta 42 mediated neurodegeneration in Drosophila eye

The Hippo Pathway Targets Rae1 to Regulate Mitosis and Organ Size and to Feed Back to Regulate Upstream Components Merlin, Hippo, and Warts

In Vitro and In Vivo Proteomic Comparison of Human Neural Progenitor Cell‐Induced Photoreceptor Survival

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