Canonical Wnt/β-Catenin Signalling Is Essential for Optic Cup Formation

Hägglund, Anna-Carin; Berghard, Anna; Carlsson, Leif

doi:10.1371/journal.pone.0081158

Cited by 54 publications

(64 citation statements)

References 73 publications

(109 reference statements)

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“…Mouse ESCs (EB5, Rx::EGFP, Rx::EGFP, 7tcf::mCherry and Rx::EGFP, 7tcf::tdTomato) were maintained as previously described (Eiraku et al, (Behesti et al, 2006;Hägglund et al, 2013;Yun et al, 2009;Furuta and Hogan, 1998;Liu et al, 2006 2011). We define the day on which the SFEBq culture was started as day 0.…”

Section: Mouse Esc Culturementioning

confidence: 99%

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: Mouse Esc Culturementioning

confidence: 99%

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

Hasegawa¹,

Takata²,

Okuda³

et al. 2016

Development

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“…3c, d’). To analyze further whether disturbing C3aR signaling affects the pathways associated with cell specification and eye morphogenesis, we decided to investigate β-catenin, a canonical Wntpathway effector which is important for RPE commitment and OC formation (Hagglund et al, 2013; Steinfeld et al, 2013; Westenskow et al, 2009). We have previously used an antibody that specifically recognizes the transcriptionally active form of β-catenin (PY-489-β- catenin) (Rhee et al, 2007; Zhu et al, 2014).…”

Section: Resultsmentioning

confidence: 99%

“…These domains are regulated by several transcription factors including Pax2, Pax6, Vax 1/2, AP-2 alpha and Tbx5 along with several signaling pathways such as Shh, BMP, Wnt, retinoic acid and FGF. Disruption of any of these during OV to OC formation results either in microphthalmia, ventral domain expansion, defective OS, retina duplications and/or coloboma (Adler and Belecky-Adams, 2002; Alldredge and Fuhrmann, 2016; Atkinson-Leadbeater et al, 2014; Bassett et al, 2010; Fujimura et al, 2009; Hagglund et al, 2013; Kobayashi et al, 2010; Koshiba-Takeuchi et al, 2000; Marsh-Armstrong et al, 1994; Molotkov et al, 2006; Morcillo et al, 2006; Mui et al, 2002, 2005; Schulte et al, 1999; Schwarz et al, 2000; Torres et al, 1996; Westenskow et al, 2009; Zhang and Yang, 2001; Zhao et al, 2010; Zhou et al, 2008). We considered defects on pathways involved in the maintenance of dorsal neuroretinal patterning of the eye such as the Wnt pathway to possibly explain the phenotype obtained by blocking/knocking down C3aR during OV formation.…”

Section: Discussionmentioning

confidence: 99%

“…We observed loss of Tbx5 and raldh-1 as well as expansion of the ventral Pax-2 and cVax domains similar to what was reported in the Lhx2-β-catenin KO mice, where the canonical Wnt pathway was disrupted before the formation of the OC. In addition, Lhx2-β-catenin KO mice also displayed a NE in place of the RPE (double NE) in the dorsal side (Hagglund et al, 2013). We found RPE to NE transformation but only in the ventral side.…”

Section: Discussionmentioning

confidence: 99%

“…Later in development, and under the influence of the lens placode, the distal region of the OV invaginates to generate a bilayered optic cup (OC) that eventually gives rise to the presumptive RPE and presumptive neural retina (NR), while the most proximal region of the OV generates the optic stalk (OS) and the optic fissure (OF) (Fuhrmann, 2010; Graw, 2010; Heavner and Pevny, 2012). Different signaling pathways and factors contribute to the establishment of the dorsal-ventral boundaries for the proper formation of the OC including fibroblast growth factor (FGF), sonic hedgehog (Shh), wingless-type MMTV integration site family (Wnt) and bone morphogenetic protein (BMP) signaling cascades as well as paired box (Pax) transcription factors such as Pax2 and Pax6 (Atkinson-Leadbeater et al, 2014; Hagglund et al, 2013; Kobayashi et al, 2010; Schwarz et al, 2000). In addition, transcription factors such as Vax1 and Vax2 (homologous to cVax in chick) are activated by Shh and cooperate with Pax2 by directly repressing Pax6 in the OS (Mui et al, 2002, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Complement component C3aR constitutes a novel regulator for chick eye morphogenesis

Grajales-Esquivel

Luz-Madrigal

Bierly

et al. 2017

Developmental Biology

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Complement components have been implicated in a wide variety of functions including neurogenesis, proliferation, cell migration, differentiation, cancer, and more recently early development and regeneration. Following our initial observations indicating that C3a/C3aR signaling induces chick retina regeneration, we analyzed its role in chick eye morphogenesis. During eye development, the optic vesicle (OV) invaginates to generate a bilayer optic cup (OC) that gives rise to the retinal pigmented epithelium (RPE) and neural retina. We show by immunofluorescence staining that C3 and the receptor for C3a (the cleaved and active form of C3), C3aR, are present in chick embryos during eye morphogenesis in the OV and OC. Interestingly, C3aR is mainly localized in the nuclear compartment at the OC stage. Loss of function studies at the OV stage using morpholinos or a blocking antibody targeting the C3aR (anti-C3aR Ab), causes eye defects such as microphthalmia and defects in the ventral portion of the eye that result in coloboma. Such defects were not observed when C3aR was disrupted at the OC stage. Histological analysis demonstrated that microphthalmic eyes were unable to generate a normal optic stalk or a closed OC. The dorsal/ventral patterning defects were accompanied by an expansion of the ventral markers Pax2, cVax and retinoic acid synthesizing enzyme raldh-3 (aldh1a3) domains, an absence of the dorsal expression of Tbx5 and raldh-1 (aldh1a1) and a re-specification of the ventral RPE to neuroepithelium. In addition, the eyes showed overall decreased expression of Gli1 and a change in distribution of nuclear β-catenin, suggesting that Shh and Wnt pathways have been affected. Finally, we observed prominent cell death along with a decrease in proliferating cells, indicating that both processes contribute to the microphthalmic phenotype. Together our results show that C3aR is necessary for the proper morphogenesis of the OC. This is the first report implicating C3aR in eye development, revealing an unsuspected hitherto regulator for proper chick eye morphogenesis.

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Reduced mTORC1‐signaling in progenitor cells leads to retinal lamination deficits

Nord,

Jones,

Garcia‐Maestre

et al. 2024

Developmental Dynamics

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BackgroundNeuronal lamination is a hallmark of the mammalian central nervous system (CNS) and underlies connectivity and function. Initial formation of this tissue architecture involves the integration of various signaling pathways that regulate the differentiation and migration of neural progenitor cells.ResultsHere, we demonstrate that mTORC1 mediates critical roles during neuronal lamination using the mouse retina as a model system. Down‐regulation of mTORC1‐signaling in retinal progenitor cells by conditional deletion of Rptor led to decreases in proliferation and increased apoptosis during embryogenesis. These developmental deficits preceded aberrant lamination in adult animals which was best exemplified by the fusion of the outer and inner nuclear layer and the absence of an outer plexiform layer. Moreover, ganglion cell axons originating from each Rptor‐ablated retina appeared to segregate to an equal degree at the optic chiasm with both contralateral and ipsilateral projections displaying overlapping termination topographies within several retinorecipient nuclei. In combination, these visual pathway defects led to visually mediated behavioral deficits.ConclusionsThis study establishes a critical role for mTORC1‐signaling during retinal lamination and demonstrates that this pathway regulates diverse developmental mechanisms involved in driving the stratified arrangement of neurons during CNS development.

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Canonical Wnt/β-Catenin Signalling Is Essential for Optic Cup Formation

Cited by 54 publications

References 73 publications

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

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

Complement component C3aR constitutes a novel regulator for chick eye morphogenesis

Reduced mTORC1‐signaling in progenitor cells leads to retinal lamination deficits

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