Establishment of the neurogenic boundary of the mouse retina requires cooperation of SOX2 and WNT signalingReportar como inadecuado




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Neural Development

, 9:27

First Online: 09 December 2014Received: 27 August 2014Accepted: 14 November 2014

Abstract

BackgroundEye development in vertebrates relies on the critical regulation of SOX2 expression. Humans with mutations in SOX2 often suffer from eye defects including anophthalmia no eye and microphthalmia small eye. In mice, deletion of Sox2 in optic cup progenitor cells results in loss of neural competence and cell fate conversion of the neural retina to a non-neurogenic fate, specifically the acquisition of fate associated with progenitors of the ciliary epithelium. This fate is also promoted with constitutive expression of stabilized β-Catenin in the optic cup, where the WNT pathway is up-regulated. We addressed whether SOX2 co-ordinates the neurogenic boundary of the retina through modulating the WNT-β-Catenin pathway by using a genetic approach in the mouse.

ResultsUpon deletion of Sox2 in the optic cup, response to WNT signaling was expanded, correlating with loss of neural competence, cell fate conversion of the neural retina to ciliary epithelium primordium and, in addition, increased cell cycle time of optic cup progenitors. Removal of Ctnnb1 rescued the cell fate conversion; however, the loss of neural competence and the proliferation defect resulting from lack of SOX2 were not overcome. Lastly, central Sox2-deficient optic cup progenitor cells exhibited WNT-independent up-regulation of D-type Cyclins.

ConclusionWe propose two distinct roles for SOX2 in the developing retina. Our findings suggest that SOX2 antagonizes the WNT pathway to maintain a neurogenic fate and, in contrast, regulates cycling of optic cup progenitors in a WNT-independent manner. Given that WNT signaling acting upstream of SOX2 has been implicated in the tumorigenicity of embryonic stem cell-derived retinal progenitor cells, our results distinguish the endogenous role of WNT signaling in early optic cup patterning and support a WNT-independent role for SOX2 in maintaining retinal progenitor cell proliferation.

Keywordsβ-Catenin Canonical WNT signaling Cell cycle Eye development Neural progenitor cells Proliferation Retina SOX2 AbbreviationsΑΝΟVΑanalysis of variance

β-galβ-galactosidase

BACbacterial artificial chromosome

BrdUbromodeoxyuridine

CBciliary body

Ccnd1CyclinD1

Ccnd3CyclinD3

CEciliary epithelium

CMciliary margin

Ctnnb1β-Catenin

Eembryonic day

ESCsembryonic stem cells

FDRfalse discovery rate

GFPgreen fluorescent protein

GOFgain-of-function

IdUiododeoxyuridine

IHCimmunohistochemistry

ISHin situ hybridization

IOPintraocular pressure

LOFloss-of-function

NRneural retina

OCoptic cup

OCPCoptic cup progenitor cell

Ppostnatal day

PADEpermutation analysis for differential expression

PCRpolymerase chain reaction

PFAparaformaldehyde

RGCretinal ganglion cell

RPCretinal progenitor cell

Seysmall-eye mutation

ShhSonic Hedgehog

TCcell cycle time

TGFβtransforming growth factor beta

TSS-phase time.

Electronic supplementary materialThe online version of this article doi:10.1186-1749-8104-9-27 contains supplementary material, which is available to authorized users.

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Autor: Whitney E Heavner - Cynthia L Andoniadou - Larysa H Pevny

Fuente: https://link.springer.com/







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