<i>Rbpj</i>Cell Autonomous Regulation of Retinal Ganglion Cell and Cone Photoreceptor Fates in the Mouse Retina

Riesenberg, Amy N.; Liu, Zhenyi; Kopan, Raphael; Brown, Nadean L.

doi:10.1523/jneurosci.3382-09.2009

Cited by 98 publications

(141 citation statements)

References 107 publications

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“…Otx2 expression is upregulated in the RBPj-null retina, suggesting that RBPj-regulated genes, including Hes and Hey genes, are involved in Otx2 gene regulation. HES1 or HES5 single knock-out mice did not exhibit overproduction of photoreceptors (Hojo et al, 2000;Takatsuka et al, 2004;Riesenberg et al, 2009), suggesting that HES and/or HEY proteins are functionally redundant in repressing Otx2 transcription. Our ChIP assay results suggest that HES1, at least, binds to EELPOT.…”

Section: Regulation Of Otx2 Transcription In Rpcs By Raxmentioning

confidence: 99%

An Essential Role for RAX Homeoprotein and NOTCH–HES Signaling inOtx2Expression in Embryonic Retinal Photoreceptor Cell Fate Determination

Muranishi¹,

Terada²,

Inoue³

et al. 2011

J. Neurosci.

117

152

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The molecular mechanisms underlying cell fate determination from common progenitors in the vertebrate CNS remain elusive. We previously reported that the OTX2 homeoprotein regulates retinal photoreceptor cell fate determination. While Otx2 transactivation is a pivotal process for photoreceptor cell fate determination, its transactivation mechanism in the retina is unknown. Here, we identified an evolutionarily conserved Otx2 enhancer of ϳ500 bp, named embryonic enhancer locus for photoreceptor Otx2 transcription (EELPOT), which can recapitulate initial Otx2 expression in the embryonic mouse retina. We found that the RAX homeoprotein interacts with EELPOT to transactivate Otx2, mainly in the final cell cycle of retinal progenitors. Conditional inactivation of Rax results in downregulation of Otx2 expression in vivo. We also showed that NOTCH-HES signaling negatively regulates EELPOT to suppress Otx2 expression. These results suggest that the integrated activity of cell-intrinsic and -extrinsic factors on EELPOT underlies the molecular basis of photoreceptor cell fate determination in the embryonic retina.

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Section: Regulation Of Otx2 Transcription In Rpcs By Raxmentioning

confidence: 99%

An Essential Role for RAX Homeoprotein and NOTCH–HES Signaling inOtx2Expression in Embryonic Retinal Photoreceptor Cell Fate Determination

Muranishi¹,

Terada²,

Inoue³

et al. 2011

J. Neurosci.

117

152

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“…The Notch signaling pathway affects the differentiation of Müller glia and cone photoreceptors in positive and negative ways (Furukawa et al, 1997;Hojo et al, 2000;Jadhav et al, 2006;Yaron et al, 2006;Riesenberg et al, 2009). We examined whether Sox4 and Sox11 affect Notch signaling by analyzing RBP-j-luciferase, a reporter for Notch signaling (Minoguchi et al, 1997).…”

Section: Gain-of-function Analysis Of Sox11 and Sox4 Revealed Alteredmentioning

confidence: 99%

The early retinal progenitor-expressed gene Sox11 regulates the timing of the differentiation of retinal cells

et al. 2013

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SUMMARYSry-related HMG box (Sox) proteins, Sox11 and Sox4 are members of the SoxC subtype. We found that Sox11 was strongly expressed in early retinal progenitor cells and that Sox4 expression began around birth, when expression of Sox11 subsided. To analyze the roles of Sox11 and Sox4 in retinal development, we perturbed their expression patterns in retinal explant cultures. Overexpression of Sox11 and Sox4 in retinal progenitors resulted in similar phenotypes: an increased number of cone cells and dramatically decreased numbers of rod cells and Müller glia. Birth-date analysis showed that cone cells were produced at a later developmental stage than that in which cone genesis normally occurs. Sox11-knockout retinas showed delayed onset and progress of differentiation of subsets of retinal cells during the embryonic period. After birth, retinal differentiation took place relatively normally, probably because of the redundant activity of Sox4, which starts to be expressed around birth. Overexpression and loss-of-function analysis failed to provide any evidence that Sox11 and Sox4 directly regulate the transcription of genes crucial to the differentiation of subsets of retinal cells. However, histone H3 acetylation of some early proneural genes was reduced in knockout retina. Thus, Sox11 may create an epigenetic state that helps to establish the competency to differentiate. Taking our findings together, we propose that the sequential expression of Sox11 and Sox4 during retinogenesis leads to the fine adjustment of retinal differentiation by helping to establish the competency of retinal progenitors.

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“…There exist three prominent phenotypes in Notch1 and Rbpj conditional mutant retinas, i.e., photoreceptor overproduction, diminished progenitor proliferation, and laminar disorganization by the formation of rosette structures (21,22,46,47). It is unclear whether these phenotypes are mediated by different Notch ligands or whether each Notch ligand can similarly mediate all these phenotypes.…”

Section: Dll4 Instead Of Dll1 Mediates Notch Signaling To Suppressmentioning

confidence: 99%

Forkhead box N4 (Foxn4) activates Dll4-Notch signaling to suppress photoreceptor cell fates of early retinal progenitors

Luo¹,

Jin²,

Xie³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The generation of diverse neuronal types and subtypes from multipotent progenitors during development is crucial for assembling functional neural circuits in the adult central nervous system. During mouse retinogenesis, early retinal progenitors give rise to several cell types, including ganglion, amacrine, horizontal, cone, and rod cells. It is unknown at present how each of these fates is selected from the multiple neuronal fates available to the early progenitor. By using a combination of bioinformatic, genetic, and biochemical approaches, we investigated the mechanism by which Foxn4 selects the amacrine and horizontal cell fates from multipotential retinal progenitors. These studies indicate that Foxn4 has an intrinsic activity to suppress the alternative photoreceptor cell fates of early retinal progenitors by selectively activating Dll4-Notch signaling. Gene expression and conditional ablation analyses reveal that Dll4 is directly activated by Foxn4 via phylogenetically conserved enhancers and that Dll4 can partly mediate the Foxn4 function by serving as a major Notch ligand to expand the progenitor pool and limit photoreceptor production. Our data together define a Foxn4-mediated molecular and signaling pathway that underlies the suppression of alternative cell fates of early retinal progenitors.

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RbpjCell Autonomous Regulation of Retinal Ganglion Cell and Cone Photoreceptor Fates in the Mouse Retina

Cited by 98 publications

References 107 publications

An Essential Role for RAX Homeoprotein and NOTCH–HES Signaling inOtx2Expression in Embryonic Retinal Photoreceptor Cell Fate Determination

An Essential Role for RAX Homeoprotein and NOTCH–HES Signaling inOtx2Expression in Embryonic Retinal Photoreceptor Cell Fate Determination

The early retinal progenitor-expressed gene Sox11 regulates the timing of the differentiation of retinal cells

Forkhead box N4 (Foxn4) activates Dll4-Notch signaling to suppress photoreceptor cell fates of early retinal progenitors

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