Ectopic Activation of Wnt/β-Catenin Signaling in Lens Fiber Cells Results in Cataract Formation and Aberrant Fiber Cell Differentiation

Antosova, Barbora; Jana, Smolikova; Borkovcova, Romana; Strnad, Hynek; Láchová, Jitka; Machoň, Ondřej; Kozmík, Zbyněk

doi:10.1371/journal.pone.0078279

Cited by 21 publications

(16 citation statements)

References 56 publications

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“…These observations fit very well to published data showing that cataract formation, smaller lenses and inhibited lens cell differentiation can be induced by β-catenin overexpression (Antosova et al, 2013;Shaham et al, 2009;Martinez et al, 2009). Note that overexpression of β-catenin in LFCs alone is sufficient to induce cataract formation (Antosova et al, 2013). Gain of β-catenin function in the central ocular ectoderm suppresses lens formation (Smith et al, 2005), which is in line with the smaller lenses found in our morphants.…”

Section: Sipa1l3 and Wnt Signalingsupporting

confidence: 92%

“…Additionally, Sipa1l3 or Epha4 deficiency resulted in an upregulation of the direct Wnt/β-catenin target axin2, which is in agreement with a previously published study that shows axin2 overexpression upon Wnt/β-catenin activation in mouse lenses (Antosova et al, 2013). These observations fit very well to published data showing that cataract formation, smaller lenses and inhibited lens cell differentiation can be induced by β-catenin overexpression (Antosova et al, 2013;Shaham et al, 2009;Martinez et al, 2009).…”

Section: Sipa1l3 and Wnt Signalingsupporting

confidence: 92%

“…Interaction of Epha4 and Sipa1l3 causes proper eye development through β-catenin-independent Wnt signaling In studies previously published by others, it has been shown that overexpression of β-catenin in LFCs results in an inhibition of LFC differentiation and cataract formation (Antosova et al, 2013;Shaham et al, 2009) that is similar to the Sipa1l3 LOF phenotype in the mouse (Greenlees et al, 2015). Gain of β-catenin function in the lens also leads to microphthalmia (Martinez et al, 2009) comparable to the loss of Sipa1l3 phenotype ( Fig.…”

Section: Loss Of Sipa1l3 and Epha4 Function Influence Early Eye Develmentioning

confidence: 73%

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An Epha4/Sipa1l3/Wnt pathway regulates eye development and lens maturation

et al. 2016

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The signal-induced proliferation-associated family of proteins comprises four members, SIPA1 and SIPA1L1-3. Mutations of the human SIPA1L3 gene result in congenital cataracts. In Xenopus, loss of Sipa1l3 function led to a severe eye phenotype that was distinguished by smaller eyes and lenses including lens fiber cell maturation defects. We found a direct interaction between Sipa1l3 and Epha4, building a functional platform for proper ocular development. Epha4 deficiency phenocopied loss of Sipa1l3 and rescue experiments demonstrated that Epha4 acts upstream of Sipa1l3 during eye development, with both Sipa1l3 and Epha4 required for early eye specification. The ocular phenotype, upon loss of either Epha4 or Sipa1l3, was partially mediated by rax. We demonstrate that canonical Wnt signaling is inhibited downstream of Epha4 and Sipa1l3 during normal eye development. Depletion of either Sipa1l3 or Epha4 resulted in an upregulation of axin2 expression, a direct Wnt/β-catenin target gene. In line with this, Sipa1l3 or Epha4 depletion could be rescued by blocking Wnt/β-catenin or activating non-canonical Wnt signaling. We therefore conclude that this pathomechanism prevents proper eye development and maturation of lens fiber cells, resulting in congenital cataracts.

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Section: Sipa1l3 and Wnt Signalingsupporting

confidence: 92%

Section: Sipa1l3 and Wnt Signalingsupporting

confidence: 92%

Section: Loss Of Sipa1l3 and Epha4 Function Influence Early Eye Develmentioning

confidence: 73%

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An Epha4/Sipa1l3/Wnt pathway regulates eye development and lens maturation

et al. 2016

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“…Our results resemble more the phenotype obtained when Axin2, an antagonist of Wnt/β-catenin, is disrupted leading to developmental eye defects such as microphthalmia, lens defects and coloboma including defects in the closure of the OF and ventral OC (Alldredge and Fuhrmann, 2016). Moreover, constitutive activation of Wnt/β-catenin signaling in lens fiber cells results in abnormal and delayed fiber cell differentiation resulting in cataracts and microphthalmia (Antosova et al, 2013). Finally, we have previously observed that nuclear β-catenin+ and p27+ (Cyclin-dependent kinase inhibitor 1B) cells of the RPE do not proliferate suggesting that nuclear β-catenin prevents those cells from entering the cell cycle (Zhu et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

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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“…It is urgent to seek the underlying molecular mechanisms of neuronal dysfunction induced by neuroinflammation. Wnt signaling pathway, proven to be involved in a variety of functions in cellular processes, including proliferation, differentiation, and apoptosis (Antosova et al 2013;Wei et al 2013;Xie et al 2014), is closely associated with the development of the CNS embryonic development and the regulation of the adult brain function . In detail, it regulates synaptic plasticity and neurogenesis in the adult nervous system.…”

Section: Introductionmentioning

confidence: 99%

Up-Regulation of Corticocerebral NKD2 in Lipopolysaccharide-Induced Neuroinflammation

et al. 2015

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Naked2 (NKD2), one member of Naked family, has been shown to negatively regulate Wnt/β-catenin signaling pathway. It has been recognized that NKD2 plays a vital role in cell homeostasis and prevention of tumorigenesis. However, NKD2 expression and its functional role in the brain in neuroinflammatory processes remain unclear. In our study, we investigated NKD2 distribution and role in lipopolysaccharide (LPS)-induced neuroinflammation rat model. The data indicated that NKD2 was up-regulated in LPS-injected brain, and the cellular localization of NKD2 was predominantly in cerebral cortical neurons. Furthermore, we treated primary neurons with conditioned media (CM) collected from LPS-stimulated mixed glial cultures (MGC). We detected that the up-regulation of NKD2 might be associated with the subsequent apoptosis in neurons. We also found knockdown NKD2 partially depressed the increase of cleaved caspase-3 and increased the reduction of β-catenin stimulated by MGC-CM. Taken together, these results suggested that NKD2 might be involved in neuronal apoptosis via the Wnt/β-catenin pathway during neuroinflammation in CNS. Our findings might provide a new therapeutic target for the prevention of neuroinflammation-involved neurological disorders.

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Ectopic Activation of Wnt/β-Catenin Signaling in Lens Fiber Cells Results in Cataract Formation and Aberrant Fiber Cell Differentiation

Cited by 21 publications

References 56 publications

An Epha4/Sipa1l3/Wnt pathway regulates eye development and lens maturation

An Epha4/Sipa1l3/Wnt pathway regulates eye development and lens maturation

Complement component C3aR constitutes a novel regulator for chick eye morphogenesis

Up-Regulation of Corticocerebral NKD2 in Lipopolysaccharide-Induced Neuroinflammation

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