mTORC1 accelerates retinal development via the immunoproteasome

Choi, Ji-heon; Jo, Hong Seok; Lim, Soyeon; Kim, Hyoung-Tai; Lee, Kang Woo; Moon, Kyeong Hwan; Ha, Taejeong; Kwak, Sang Soo; Kim, Yeha; Lee, Eun Jung; Joe, Cheol O.; Kim, Jin Woo

doi:10.1038/s41467-018-04774-9

Cited by 33 publications

(42 citation statements)

References 64 publications

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“…Subsequently, similar approaches to perturb the pathway demonstrated its involvement elsewhere in the CNS, including in the regeneration of axons in the corticospinal tracts (Du et al, 2015;Liu et al, 2010;Zukor et al, 2013). We demonstrate that, much like in rodents, the mTOR pathway plays an important role in the development of hRGCs (Choi et al, 2019) and regeneration of their axons (Park et al, 2008), and is therefore an important molecular target for establishing a disease model of glaucomatous degeneration and therapeutic RGC regeneration. This premise is supported by the following observations.…”

Section: Discussionmentioning

confidence: 70%

Human retinal ganglion cell axon regeneration by recapitulating developmental mechanisms: effects of recruitment of the mTOR pathway

et al. 2019

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The poor axon regeneration in the central nervous system (CNS) often leads to permanent functional deficit following disease or injury. For example, degeneration of retinal ganglion cell (RGC) axons in glaucoma leads to irreversible loss of vision. Here, we have tested the hypothesis that the mTOR pathway regulates the development of human RGCs and that its recruitment after injury facilitates axon regeneration. We observed that the mTOR pathway is active during RGC differentiation, and using the induced pluripotent stem cell model of neurogenesis show that it facilitates the differentiation, function and neuritogenesis of human RGCs. Using a microfluidic model, we demonstrate that recruitment of the mTOR pathway facilitates human RGC axon regeneration after axotomy, providing evidence that the recapitulation of developmental mechanism(s) might be a viable approach for facilitating axon regeneration in the diseased or injured human CNS, thus helping to reduce and/or recover loss of function.

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Section: Discussionmentioning

confidence: 70%

Human retinal ganglion cell axon regeneration by recapitulating developmental mechanisms: effects of recruitment of the mTOR pathway

et al. 2019

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“…MTORC1 signaling was also enriched and is known to crosstalk with the Hippo pathway ( Tumaneng et al, 2012 ). The phosphatidylinositol 3-kinase (PI3K)-Akt-mTORC1 pathway has been discovered to promote mouse RPC proliferation by regulating the synthesis and degradation of CYCLIN proteins with the interesting exception of CYCLIN D1 ( Choi et al, 2018 ). MTOR was also shown to be required for chick MG proliferation in response to damage ( Zelinka et al, 2016 ).…”

Section: Resultsmentioning

confidence: 99%

The Hippo Pathway Blocks Mammalian Retinal Müller Glial Cell Reprogramming

et al. 2019

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SUMMARY In response to retinal damage, the Müller glial cells (MGs) of the zebrafish retina have the ability to undergo a cellular reprogramming event in which they enter the cell cycle and divide asymmetrically, thereby producing multipotent retinal progenitors capable of regenerating lost retinal neurons. However, mammalian MGs do not exhibit such a proliferative and regenerative ability. Here, we identify Hippo pathway-mediated repression of the transcription cofactor YAP as a core regulatory mechanism that normally blocks mammalian MG proliferation and cellular reprogramming. MG-specific deletion of Hippo pathway components Lats1 and Lats2 , as well as transgenic expression of a Hippo non-responsive form of YAP (YAP5SA), resulted in dramatic Cyclin D1 upregulation, loss of adult MG identity, and attainment of a highly proliferative, progenitor-like cellular state. Our results reveal that mammalian MGs may have latent regenerative capacity that can be stimulated by repressing Hippo signaling.

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“…It was shown that mTOR regulated the proliferation and differentiation of retinal progenitor cells in the ciliary marginal zone in Xenopus (Love, Keshavan, Lewis, Harris, & Agathocleous, 2014). A recent study also reported that mTORC1 accelerated the cell cycle progression and neurogenesis of retinal progenitors via the immunoproteasome during mouse development (Choi et al, 2018).…”

Section: Introductionmentioning

confidence: 97%

Inflammation‐induced mammalian target of rapamycin signaling is essential for retina regeneration

Zhang

Hou

et al. 2019

Glia

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Upon retina injury, Müller glia in the zebrafish retina respond by generating multipotent progenitors to repair the retina. However, the complete mechanisms underlying retina regeneration remain elusive. Here we report inflammation‐induced mammalian target of rapamycin (mTOR) signaling in the Müller glia is essential for retina regeneration in adult zebrafish. We show after a stab injury, mTOR is rapidly activated in Müller glia and later Müller glia‐derived progenitor cells (MGPCs). Importantly, mTOR is required for Müller glia dedifferentiation, as well as the proliferation of Müller glia and MGPCs. Interestingly, transient mTOR inhibition by rapamycin only reversibly suppresses MGPC proliferation, while its longer suppression by knocking down Raptor significantly inhibits the regeneration of retinal neurons. We further show mTOR promotes retina regeneration by regulating the mRNA expression of key reprogramming factors ascl1a and lin‐28a, cell cycle‐related genes and critical cytokines. Surprisingly, we identify microglia/macrophage‐mediated inflammation as an important upstream regulator of mTOR in the Müller glia and it promotes retina regeneration through mTOR. Our study not only demonstrates the important functions of mTOR but also reveals an interesting link between inflammation and the mTOR signaling during retina regeneration.

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mTORC1 accelerates retinal development via the immunoproteasome

Cited by 33 publications

References 64 publications

Human retinal ganglion cell axon regeneration by recapitulating developmental mechanisms: effects of recruitment of the mTOR pathway

Human retinal ganglion cell axon regeneration by recapitulating developmental mechanisms: effects of recruitment of the mTOR pathway

The Hippo Pathway Blocks Mammalian Retinal Müller Glial Cell Reprogramming

Inflammation‐induced mammalian target of rapamycin signaling is essential for retina regeneration

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