Multiple intrinsic factors act in concert with Lhx2 to direct retinal gliogenesis

Melo, Jimmy de; Clark, Brian S.; Blackshaw, Seth

doi:10.1038/srep32757

Cited by 34 publications

(55 citation statements)

References 54 publications

(95 reference statements)

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“…It is interesting to note that many of these genes are also active in the developing retina (de Melo, Clark, & Blackshaw, ), and that we have found NFIA to be expressed in both Müller glia and astrocytes in the developing and mature retina, suggesting a similar role for NFIA in gliogensis in the retina. Indeed, NFIA overexpression in early postnatal retinal progenitor cells promotes the formation of cells with Müller glia‐like radial morphology (de Melo et al, ), although overexpression itself is not sufficient to create mature glial cells.…”

Section: Discussionmentioning

confidence: 52%

“…As a key player in the differentiation of glial populations, NFIA interacts with many other known transcription factors that participate in this process, such as Hes1, Lhx2, Sox9, and Sox10, as well as influencing the Notch pathway in progenitor cells (Piper et al, 2010;Subramanian et al, 2011;Kang et al, 2012;Glasgow et al, 2014). It is interesting to note that many of these genes are also active in the developing retina (de Melo, Clark, & Blackshaw, 2016), and that we have found NFIA to be expressed in both M€ uller glia and astrocytes in the developing and mature retina, NFIA does not just affect glial populations, however, as it appears to play a role in neuronal development as well (Plachez et al, 2008).…”

Section: Discussionmentioning

confidence: 80%

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DNER and NFIA are expressed by developing and mature AII amacrine cells in the mouse retina

Keeley

Reese

2017

J of Comparative Neurology

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The present study has taken advantage of publicly available cell type specific mRNA expression databases in order to identify potential genes participating in the development of retinal AII amacrine cells. We profile two such genes, Delta/Notch-like EGF repeat containing (Dner) and nuclear factor I/A (Nfia), that are each heavily expressed in AII amacrine cells in the mature mouse retina, and which conjointly identify this retinal cell population in its entirety when using antibodies to DNER and NFIA. DNER is present on the plasma membrane, while NFIA is confined to the nucleus, consistent with known functions of each of these two proteins. DNER also identifies some other subsets of retinal ganglion and amacrine cell types, along with horizontal cells, while NFIA identifies a subset of bipolar cells as well as Muller glia and astrocytes. During early postnatal development, NFIA labels astrocytes on the day of birth, AII amacrine cells at postnatal (P) day 5, and Muller glia by P10, when horizontal cells also transiently exhibit NFIA immunofluorescence. DNER, by contrast, is present in ganglion and amacrine cells on P1, also labeling the horizontal cells by P10. Developing AII amacrine cells exhibit accumulating DNER labeling at the dendritic stalk, labeling that becomes progressively conspicuous by P10, as it is in maturity. This developmental time course is consistent with a prospective role for each gene in the differentiation of AII amacrine cells.

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Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 80%

DNER and NFIA are expressed by developing and mature AII amacrine cells in the mouse retina

Keeley

Reese

2017

J of Comparative Neurology

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“…While constitutive activation of Notch permissively maintains cells in a RPC like state, Lhx2 regulation of Notch controls MG differentiation. The retinas of Lhx2 knockout mice lack Notch signaling and MG, but this phenotype can be rescued by the expression of the NICD [52]. Notably, overexpression of the potently gliogenic Hes5 is insufficient for rescue, indicating that multiple Notch target genes are involved in the specification of MG.…”

Section: Mg Specificationmentioning

confidence: 99%

The Regulation of Notch Signaling in Retinal Development and Regeneration

Mills

Goldman

2017

Curr Pathobiol Rep

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Purpose of review Notch signaling is an important component of retinal progenitor cell maintenance and MG specification during development, and its manipulation may be critical for allowing MG to re-enter the cell cycle and regenerate neurons in adults. In mammals, MG respond to retinal injury by undergoing a gliotic response rather than a regenerative one. Understanding the complexities of Notch signaling may allow for strategies that enhance regeneration over gliosis. Recent findings Notch signaling is regulated at multiple levels, and is interdependent with various other signaling pathways in both the receptor and ligand expressing cells. The precise spatial and temporal patterning of Notch components is necessary for proper retinal development. Regenerative species undergo a dynamic regulation of Notch signaling in MG upon injury, whereas non-regenerative species fail to productively regulate Notch. Summary Notch signaling is malleable, such that the altered composition of growth and transcription factors in the developing and mature retinas result in different Notch mediated responses. Successful regeneration will require the manipulation of the retinal environment to foster a dynamic rather than static regulation of Notch signaling in concert with other reprogramming and differentiation factors.

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“…Retinas were electroporated at P0 as previously described (7,11) and harvested for analysis at P1, P2, or P14. In situ hybridization was performed as previously described (34).…”

Section: Electroporation Immunohistochemistry In Situ Hybridizationmentioning

confidence: 99%

“…Lhx2ΔcKO at later timepoints yields disrupted Müller differentiation, leading to morphological abnormalities and a loss of MG-specific gene expression (7,11).…”

Section: Introductionmentioning

confidence: 99%

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

Melo

Venkataraman

Zibetti

et al. 2017

Preprint

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Precise 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 Lhx2All rights reserved. No reuse allowed without permission.was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/183285 doi: bioRxiv preprint first posted online Sep. 1, 2017; 2 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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Multiple intrinsic factors act in concert with Lhx2 to direct retinal gliogenesis

Cited by 34 publications

References 54 publications

DNER and NFIA are expressed by developing and mature AII amacrine cells in the mouse retina

DNER and NFIA are expressed by developing and mature AII amacrine cells in the mouse retina

The Regulation of Notch Signaling in Retinal Development and Regeneration

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

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