LHX2 Interacts with the NuRD Complex and Regulates Cortical Neuron Subtype Determinants
            <i>Fezf2</i>
            and
            <i>Sox11</i>

Muralidharan, Bhavana; Khatri, Zeba; Maheshwari, Upasana; Gupta, Ritika; Roy, Basabdatta; Pradhan, Saurabh J.; Karmodiya, Krishanpal; Padmanabhan, Hari; Shetty, Ashwin S.; Balaji, Chinthapalli; Kolthur‐Seetharam, Ullas; Macklis, Jeffrey D.; Galande, Sanjeev; Tole, Shubha

doi:10.1523/jneurosci.2836-16.2017

Cited by 22 publications

(27 citation statements)

References 2 publications

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“…By reconstituting the expression of transcription factors that are induced in astrocytes maturing in vivo but are missing from cultured astrocytes, we could demonstrate a maturation-promoting activity of four factors, Rorb, Dbx2, Lhx2 and Fezf2. These factors have mainly been studied for their roles in neuronal subtype specification (Chen et al, 2008;Muralidharan et al, 2017;Oishi et al, 2016;Pierani et al, 1999). Interestingly, their roles in neurons seem to be mediated at least partially by cross-repression of alternative neuronal subtype programmes, suggesting that their expression in astrocytes might contribute to the global suppression of neuronal programmes.…”

Section: Discussionmentioning

confidence: 99%

Extensive transcriptional and chromatin changes underlie astrocyte maturationin vivoand in culture

Lattke

Goldstone

Guillemot

2020

Preprint

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Astrocytes have diverse functions in brain homeostasis. Many of these functions are acquired during late stages of differentiation when astrocytes become fully mature. The mechanisms underlying astrocyte maturation are not well understood. Here we identified extensive transcriptional changes that occur during astrocyte maturation and are accompanied by chromatin remodelling at enhancer elements. Investigating astrocyte maturation in a cell culture model revealed that in vitro-differentiated astrocytes lacked expression of many mature astrocyte-specific genes, including genes for the transcription factors Rorb, Dbx2, Lhx2 and Fezf2. Forced expression of these factors in vitro induced distinct sets of mature astrocytesspecific transcripts. Culturing astrocytes with FGF2 in a three-dimensional gel induced expression of Rorb, Dbx2 and Lhx2 and improved their maturity based on transcriptional and chromatin profiles. Therefore extrinsic signals orchestrate the expression of multiple intrinsic regulators, which in turn induce in a modular manner the transcriptional and chromatin changes underlying astrocyte maturation.

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Section: Discussionmentioning

confidence: 99%

Extensive transcriptional and chromatin changes underlie astrocyte maturationin vivoand in culture

Lattke

Goldstone

Guillemot

2020

Preprint

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“…We further demonstrate that these effects are dependent on Lhx2-dependent regulation of the expression of multiple proneural bHLH factors. We also show that Rnf12, which specifically ubiquitinates LDB proteins and targets them for proteolysis, is both necessary and sufficient to promote Müller glial development, and does so in a strictly Lhx2-dependent including the HDAC and NuRD protein complexes (23,31). RNF12 itself can directly bind both LHX2 and SIN3A, leading to recruitment of HDAC proteins (23).…”

Section: Furthermore Lhx2 Directly Activates Expression Of Notch-regmentioning

confidence: 76%

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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“…The precise molecular mechanism by which Lhx2 mediates these developmentally dynamic changes in chromatin accessibility is unclear. However, recent studies of Lhx2 function in developing cortex have identified multiple histone modifying enzymes that interact with Lhx2 (23) . Interestingly, these include NuRD complex components that are associated with transcriptional repression and reduced chromatin accessibility, such as LSD1, HDAC2, and RBBP4.…”

Section: Discussionmentioning

confidence: 99%

Lhx2 regulates temporal changes in chromatin accessibility and transcription factor binding in retinal progenitor cells

Zibetti

Liu

Wan

et al. 2017

Preprint

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LHX2 Interacts with the NuRD Complex and Regulates Cortical Neuron Subtype Determinants Fezf2 and Sox11

Cited by 22 publications

References 2 publications

Extensive transcriptional and chromatin changes underlie astrocyte maturationin vivoand in culture

Extensive transcriptional and chromatin changes underlie astrocyte maturationin vivoand in culture

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

Lhx2 regulates temporal changes in chromatin accessibility and transcription factor binding in retinal progenitor cells

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