Exogenous transcription factor in Müller glia enhances damage-induced neuroregeneration in mouse retina

AbstractMüller glia can serve as a source for retinal regeneration in some non-mammalian vertebrates. Recently we found that this process can be induced in mouse Müller glia after injury, by combining transgenic expression of the proneural transcription factor Ascl1 and the HDAC inhibitor TSA. However, new neurons are only generated from a subset of Müller glia in this model, and identifying factors that limit Ascl1-mediated MG reprogramming could potentially make this process more efficient, and potentially useful clinically. One factor that limits neurogenesis in some non-mammalian vertebrates is the STAT pathway activation that occurs in Müller glia in response to injury. In this report, we tested whether injury induced STAT activation hampers the ability of Ascl1 to reprogram Müller glia into retinal neurons. Using a STAT inhibitor, in combination with our previously described reprogramming paradigm, we found a large increase in the ability of Müller glia to generate neurons, similar to those we described previously. Single-cell RNA-seq showed that the progenitor-like cells derived from Ascl1-expressing Müller glia have a higher level of STAT signaling than those that become neurons. Using Ascl1 ChIP-seq and DNase-seq, we found that developmentally inappropriate Ascl1 binding sites (that were unique to the overexpression context) had enrichment for the STAT binding motif. This study provides evidence that STAT pathway activation reduces the efficiency of Ascl1-mediated reprogramming in Müller glia, potentially by directing Ascl1 to inappropriate targets.

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Ldb1 and Rnf12-dependent regulation of Lhx2 controls the relative balance between neurogenesis and gliogenesis in retina

10.1101/183285 ◽

2017 ◽

Cited By ~ 1

Author(s):

Jimmy de Melo ◽

Anand Venkataraman ◽

Brian S. Clark ◽

Cristina Zibetti ◽

Seth Blackshaw

Keyword(s):

Transcription Factor ◽

Molecular Mechanisms ◽

Critical Role ◽

Amacrine Cells ◽

Negative Regulator ◽

Wide Field ◽

Muller Glia ◽

Müller Glia ◽

Retinal Neurons ◽

Bhlh Factors

AbstractPrecise control of the relative ratio of retinal neurons and glia generated during development is essential for visual function. We show that Lhx2, which encodes a LIM-homeodomain transcription factor essential for specification and differentiation of retinal Müller glia, also plays a critical role in the development of retinal neurons. Overexpression of Lhx2, and its transcriptional coactivator Ldb1, triggers cell cycle exit and inhibits both Notch signaling and retinal gliogenesis. Lhx2/Ldb1 overexpression also induced the formation of wide-field amacrine cells (wfACs). In contrast Rnf12, which encodes a negative regulator of LDB1, is necessary for the initiation of retinal gliogenesis. We also show that LHX2 protein binds upstream of multiple neurogenic bHLH factors including Ascl1 and Neurog2, which are necessary for suppression of gliogenesis and wfAC formation respectively, and activates their expression. Finally, we demonstrate that the relative level of the LHX2-LDB1 complex in the retina decreases in tandem with the onset of gliogenesis. These findings show that control of Lhx2 function by Ldb1 and Rnf12 acts as a molecular mechanism underpinning the coordinated differentiation of neurons and Müller glia in postnatal retina.Significance StatementThe molecular mechanisms that control the ratio neurons and glia that are generated by neuronal progenitors remain unclear. Here we show that Lhx2, a transcription factor essential for retinal gliogenesis, also controls development of retinal neurons. The Lhx2 coactivator Ldb1 promotes Lhx2-dependent neurogenesis, while the Lhx2 corepressor Rnf12 is necessary and sufficient for retinal gliogenesis. Furthermore, Lhx2 directly regulates expression of bHLH factors that promote neural development, which are necessary for Lhx2-dependent neurogenesis. Finally, we show that levels of the LHX2-LDB1 complex, which activates transcription, drop as gliogenesis begins. Dynamic regulation of Lhx2 activity by Ldb1 and Rnf12 thus controls the relative levels of retinal neurogenesis and gliogenesis, and may have similar functions elsewhere in the developing nervous system.

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Pax6-positive müller glia cells express cell cycle markers but do not proliferate after photoreceptor injury in the mouse retina

Glia ◽

10.1002/glia.21174 ◽

2011 ◽

Vol 59 (7) ◽

pp. 1033-1046 ◽

Cited By ~ 42

Author(s):

Sandrine Joly ◽

Vincent Pernet ◽

Marijana Samardzija ◽

Christian Grimm

Keyword(s):

Cell Cycle ◽

Mouse Retina ◽

Muller Glia ◽

Müller Glia ◽

Glia Cells ◽

Express Cell

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bFGF and insulin lead to migration of Müller glia to photoreceptor layer in rd1 mouse retina

Neuroscience Letters ◽

10.1016/j.neulet.2021.135936 ◽

2021 ◽

Vol 755 ◽

pp. 135936

Author(s):

Manvi Goel ◽

Narender K. Dhingra

Keyword(s):

Mouse Retina ◽

Muller Glia ◽

Müller Glia ◽

Photoreceptor Layer ◽

Rd1 Mouse

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Anatomy and spatial organization of Müller glia in mouse retina

The Journal of Comparative Neurology ◽

10.1002/cne.24210 ◽

2017 ◽

Vol 525 (8) ◽

pp. spc1-spc1 ◽

Cited By ~ 1

Author(s):

Jingjing Wang ◽

Matthew L. O’Sullivan ◽

Dibyendu Mukherjee ◽

Vanessa M. Puñal ◽

Sina Farsiu ◽

...

Keyword(s):

Spatial Organization ◽

Mouse Retina ◽

Muller Glia ◽

Müller Glia

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STAT Signaling Modifies Ascl1 Chromatin Binding and Limits Neural Regeneration from Muller Glia in Adult Mouse Retina

Cell Reports ◽

10.1016/j.celrep.2020.01.075 ◽

2020 ◽

Vol 30 (7) ◽

pp. 2195-2208.e5 ◽

Cited By ~ 8

Author(s):

Nikolas L. Jorstad ◽

Matthew S. Wilken ◽

Levi Todd ◽

Connor Finkbeiner ◽

Paul Nakamura ◽

...

Keyword(s):

Adult Mouse ◽

Neural Regeneration ◽

Mouse Retina ◽

Muller Glia ◽

Chromatin Binding ◽

Müller Glia ◽

Stat Signaling

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mTORC1-induced retinal progenitor cell overproliferation leads to accelerated mitotic aging and degeneration of descendent Müller glia

eLife ◽

10.7554/elife.70079 ◽

2021 ◽

Vol 10 ◽

Author(s):

Soyeon Lim ◽

You-Joung Kim ◽

Sooyeon Park ◽

Ji-heon Choi ◽

Younghoon Sung ◽

...

Keyword(s):

Gene Expression ◽

Cell Death ◽

Tuberous Sclerosis Complex ◽

Progenitor Cell ◽

Mouse Retina ◽

Muller Glia ◽

Müller Glia ◽

Retinal Progenitor ◽

Mechanistic Target Of Rapamycin ◽

Glycolytic Gene

Retinal progenitor cells (RPCs) divide in limited numbers to generate the cells comprising vertebrate retina. The molecular mechanism that leads RPC to the division limit, however, remains elusive. Here, we find that the hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) in an RPC subset by deletion of tuberous sclerosis complex 1 (Tsc1) makes the RPCs arrive at the division limit precociously and produce Müller glia (MG) that degenerate from senescence-associated cell death. We further show the hyperproliferation of Tsc1-deficient RPCs and the degeneration of MG in the mouse retina disappear by concomitant deletion of hypoxia-induced factor 1-a (Hif1a), which induces glycolytic gene expression to support mTORC1-induced RPC proliferation. Collectively, our results suggest that, by having mTORC1 constitutively active, an RPC divides and exhausts mitotic capacity faster than neighboring RPCs, and thus produces retinal cells that degenerate with aging-related changes.

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