Ocular coloboma and dorsoventral neuroretinal patterning defects in Lrp6 mutant eyes

Zhou, Chengji J.; Molotkov, Andrei; Song, Lanying; Li, Yunhong; Pleasure, David E; Pleasure, Samuel J.; Wang, Ya Zhou

doi:10.1002/dvdy.21770

Cited by 59 publications

(66 citation statements)

References 39 publications

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“…4C,D), suggesting that canonical Wnt signaling is essential for dorsal induction and maintenance. The necessity of canonical Wnt signaling for maintenance of dorsal identity has already been reported (Veien et al, 2008;Zhou et al, 2008;Hägglund et al, 2013). In this study, we visualized canonical Wnt signaling dynamics.…”

Section: Canonical Wnt Signaling Locally Activates the Bmp Signaling mentioning

confidence: 71%

“…Wnt2b (Wnt13) is localized in dorsal RPE at an early optic vesicle stage in mice and chicks (Cho and Cepko, 2006;Steinfeld et al, 2013). In mice deficient in the Wnt receptor or its downstream component, dorsal retinal markers such as Bmp4 and Tbx5 are diminished (Zhou et al, 2008;Esteve et al, 2011;Hägglund et al, 2013). Although these previous reports suggest that both BMP signaling and canonical Wnt signaling profoundly affect the dorsal retinal specification, the underlying mechanisms of crosstalk between these signals are poorly understood.…”

Section: Introductionmentioning

confidence: 99%

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Emergence of dorsal-ventral polarity in ESC-derived retinal tissue

Hasegawa¹,

Takata²,

Okuda³

et al. 2016

Development

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We previously demonstrated that mouse embryonic stem cell (mESC)-derived retinal epithelium self-forms an optic cup-like structure. In the developing retina, the dorsal and ventral sides differ in terms of local gene expression and morphological features. This aspect has not yet been shown in vitro. Here, we demonstrate that mESC-derived retinal tissue spontaneously acquires polarity reminiscent of the dorsal-ventral (D-V) patterning of the embryonic retina. Tbx5 and Vax2 were expressed in a mutually exclusive manner, as seen in vivo. Three-dimensional morphometric analysis showed that the in vitro-formed optic cup often contains cleft structures resembling the embryonic optic fissure. To elucidate the mechanisms underlying the spontaneous D-V polarization of mESCderived retina, we examined the effects of patterning factors, and found that endogenous BMP signaling plays a predominant role in the dorsal specification. Further analysis revealed that canonical Wnt signaling, which was spontaneously activated at the proximal region, acts upstream of BMP signaling for dorsal specification. These observations suggest that D-V polarity could be established within the self-formed retinal neuroepithelium by intrinsic mechanisms involving the spatiotemporal regulation of canonical Wnt and BMP signals.

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Section: Canonical Wnt Signaling Locally Activates the Bmp Signaling mentioning

confidence: 71%

Section: Introductionmentioning

confidence: 99%

Emergence of dorsal-ventral polarity in ESC-derived retinal tissue

Hasegawa¹,

Takata²,

Okuda³

et al. 2016

Development

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“…4). In support of this, eye pigmentation appears normal in mutant mice, where the coreceptors of the Wnt/β-catenin signalling pathway, Lrp5 and 6, are mutated (Fujino et al, 2003;Zhou et al, 2008). Moreover, ectopic RESEARCH ARTICLE Development (2013) activation of the Wnt/β-catenin signalling pathway alone is not sufficient to induce MITF expression (Westenskow et al, 2010) and instead eye development and optic cup formation is disrupted (Smith et al, 2005;Fu et al, 2006;Miller et al, 2006;Fujimura et al, 2009).…”

Section: Bmp and Wnt Ligands Expressed In The Surface Ectoderm Specifmentioning

confidence: 99%

RPE specification in the chick is mediated by surface ectoderm-derived BMP and Wnt signalling

Steinfeld

Coronato

et al. 2013

Development

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The retinal pigment epithelium (RPE) is indispensable for vertebrate eye development and vision. In the classical model of optic vesicle patterning, the surface ectoderm produces fibroblast growth factors (FGFs) that specify the neural retina (NR) distally, whereas TGFβ family members released from the proximal mesenchyme are involved in RPE specification. However, we previously proposed that bone morphogenetic proteins (BMPs) released from the surface ectoderm are essential for RPE specification in chick. We now show that the BMP-and Wnt-expressing surface ectoderm is required for RPE specification. We reveal that Wnt signalling from the overlying surface ectoderm is involved in restricting BMP-mediated RPE specification to the dorsal optic vesicle. Wnt2b is expressed in the dorsal surface ectoderm and subsequently in dorsal optic vesicle cells. Activation of Wnt signalling by implanting Wnt3a-soaked beads or inhibiting GSK3β at optic vesicle stages inhibits NR development and converts the entire optic vesicle into RPE. Surface ectoderm removal at early optic vesicle stages or inhibition of Wnt, but not Wnt/β-catenin, signalling prevents pigmentation and downregulates the RPE regulatory gene Mitf. Activation of BMP or Wnt signalling can replace the surface ectoderm to rescue MITF expression and optic cup formation. We provide evidence that BMPs and Wnts cooperate via a GSK3β-dependent but β-catenin-independent pathway at the level of pSmad to ensure RPE specification in dorsal optic vesicle cells. We propose a new dorsoventral model of optic vesicle patterning, whereby initially surface ectoderm-derived Wnt signalling directs dorsal optic vesicle cells to develop into RPE through a stabilising effect of BMP signalling.

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“…However, several of these PCP signaling molecules, such as Fzds and Dvls, are also essential components of the canonical Wnt/β-catenin signaling pathway (MacDonald et al, 2009). In addition, Lrp6 is a key co-receptor in the canonical Wnt pathway and is required for a wide range of organogenetic events, including neural tube closure in mice (Carter et al, 2005;Kokubu et al, 2004;Mao et al, 2001;Pinson et al, 2000;Song et al, 2009;Song et al, 2010;Tamai et al, 2000;Wehrli et al, 2000;Zhou et al, 2008;Zhou et al, 2004;Zhou et al, 2010). However, Lrp6 is also implicated in convergent extension during Xenopus gastrulation (Tahinci et al, 2007) and may mediate non-canonical Wnt signaling for neural tube closure (Gray et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

β-catenin regulates Pax3 and Cdx2 for caudal neural tube closure and elongation

et al. 2014

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Non-canonical Wnt/planar cell polarity (PCP) signaling plays a primary role in the convergent extension that drives neural tube closure and body axis elongation. PCP signaling gene mutations cause severe neural tube defects (NTDs). However, the role of canonical Wnt/β-catenin signaling in neural tube closure and NTDs remains poorly understood. This study shows that conditional gene targeting of β-catenin in the dorsal neural folds of mouse embryos represses the expression of the homeobox-containing genes Pax3 and Cdx2 at the dorsal posterior neuropore (PNP), and subsequently diminishes the expression of the Wnt/β-catenin signaling target genes T, Tbx6 and Fgf8 at the tail bud, leading to spina bifida aperta, caudal axis bending and tail truncation. We demonstrate that Pax3 and Cdx2 are novel downstream targets of Wnt/β-catenin signaling. Transgenic activation of Pax3 cDNA can rescue the closure defect in the β-catenin mutants, suggesting that Pax3 is a key downstream effector of β-catenin signaling in the PNP closure process. Cdx2 is known to be crucial in posterior axis elongation and in neural tube closure. We found that Cdx2 expression is also repressed in the dorsal PNPs of Pax3-null embryos. However, the ectopically activated Pax3 in the β-catenin mutants cannot restore Cdx2 mRNA in the dorsal PNP, suggesting that the presence of both β-catenin and Pax3 is required for regional Cdx2 expression. Thus, β-catenin signaling is required for caudal neural tube closure and elongation, acting through the transcriptional regulation of key target genes in the PNP.

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Ocular coloboma and dorsoventral neuroretinal patterning defects in Lrp6 mutant eyes

Cited by 59 publications

References 39 publications

Emergence of dorsal-ventral polarity in ESC-derived retinal tissue

Emergence of dorsal-ventral polarity in ESC-derived retinal tissue

RPE specification in the chick is mediated by surface ectoderm-derived BMP and Wnt signalling

β-catenin regulates Pax3 and Cdx2 for caudal neural tube closure and elongation

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