Lens morphogenesis is dependent on Pax6‐mediated inhibition of the canonical Wnt/beta‐catenin signaling in the lens surface ectoderm

Machoň, Ondřej; Krešlová, Jana; Růžičková, Jana; Vacı́k, Tomáš; Klimova, Lucie; Fujimura, Naoko; Láchová, Jitka; Kozmík, Zbyněk

doi:10.1002/dvg.20583

Cited by 54 publications

(51 citation statements)

References 49 publications

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“…Interestingly, a positive role of Bcl9/9l in lens formation is in contradiction with the notion that Wnt signaling must be turned off during lens development (Smith et al 2005;Machon et al 2010). Therefore, we reasoned A GST-Bcl9-DHD1 protein, when incubated with protein extracts obtained from 12.5-dpc wild-type embryos, loses the ability to interact with Pygo2 but maintains the ability to pull down b-catenin; nonspecific signal (n.s.…”

Section: Resultsmentioning

confidence: 89%

“…It is currently widely accepted that, in the lens, the Wnt pathway must be turned off (Smith et al 2005), and a recent study discovered that this inhibition is mediated at least in part by Pax6 (Machon et al 2010). It is therefore tantalizing to speculate that Bcl9/9l and Pygo2 not only act independently from b-catenin but, together with Pax6, are involved in the inhibition of the Wnt-induced genetic program, thus ensuring that lens development proceeds correctly.…”

Section: Dhd2/dhd2mentioning

confidence: 99%

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Pax6-dependent, but β-catenin-independent, function of Bcl9 proteins in mouse lens development

et al. 2014

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Bcl9 and Bcl9l (Bcl9/9l) encode Wnt signaling components that mediate the interaction between b-catenin and Pygopus (Pygo) via two evolutionarily conserved domains, HD1 and HD2, respectively. We generated mouse strains lacking these domains to probe the b-catenin-dependent and b-catenin-independent roles of Bcl9/9l and Pygo during mouse development. While lens development is critically dependent on the presence of the HD1 domain, it is not affected by the lack of the HD2 domain, indicating that Bcl9/9l act in this context in a b-catenin-independent manner. Furthermore, we uncover a new regulatory circuit in which Pax6, the master regulator of eye development, directly activates Bcl9/9l transcription.

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Section: Resultsmentioning

confidence: 89%

Section: Dhd2/dhd2mentioning

confidence: 99%

Pax6-dependent, but β-catenin-independent, function of Bcl9 proteins in mouse lens development

et al. 2014

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“…Therefore, a correlation between Dkk1 and Pax6 might exist during optic cup development. As Cited2 controls the lens ingression process by activating Pax6 expression (Chen et al, 2008b) and Pax6 inhibits Wnt/β-catenin signaling by activation of Dkk1 expression (Machon et al, 2010), Pax6 might play a major role in the regulation of Dkk1 expression. Consequently, loss of Cited2 results in a reduced Dkk1 expression and thus explains the similar phenotype.…”

Section: Dkk1 Is Critical For Lens Invaginationmentioning

confidence: 99%

The Dkk1 dose is critical for eye development

Lieven

Rüther

2011

Developmental Biology

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During mammalian ocular development, several signaling pathways control the spatiotemporal highly defined realization of the three-dimensional eye architecture. Given the complexity of these inductive signals, the developing eye is a sensitive organ for several diseases. In this study, we investigated a Dkk1+/- haploinsufficiency during eye development, resulting in coloboma and anterior eye defects, two common developmental eye disorders. Dkk1 impacts eye development from a defined developmental time point on, and is critical for lens separation from the surface ectoderm via β-catenin mediated Pdgfrα and E-cadherin expression. Dkk1 does not impact the dorso ventral retina patterning in general but is critical for Shh dependent Pax2 extension into the midline region. The described results also indicate that the retinal Dkk1 dose is critical for important steps during eye development, such as optic fissure closure and cornea formation. Further analysis of the relationship between Dkk1 and Shh signaling revealed that Dkk1 and Shh coordinatively control anterior head formation and eye induction. During eye development itself, retinal Dkk1 activation is depending on cilia mediated Gli3 regulation. Therefore, our data essentially improve the knowledge of coloboma and anterior eye defects, which are common human eye developmental defects.

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“…Unlike BMP and FGF, activation of the Wnt/β-catenin pathway has been shown to inhibit lens fate since stabilization of β-catenin in lens primordium prevents lens formation (Kreslova et al, 2007;Machon et al, 2010;Smith et al, 2005). Activation of the Wnt/β-catenin pathway results in the accumulation of β-catenin in the nucleus, which allows the TCF/Lef family of transcription factors to activate downstream target genes.…”

Section: Pax6-deficient Rpcs Transiently Upregulate Crx Expression Bumentioning

confidence: 99%

Stage-dependent requirement of neuroretinal Pax6 for lens and retina development

Klimova

Kozmík

2014

Development

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The physical contact of optic vesicle with head surface ectoderm is an initial event triggering eye morphogenesis. This interaction leads to lens specification followed by coordinated invagination of the lens placode and optic vesicle, resulting in formation of the lens, retina and retinal pigmented epithelium. Although the role of Pax6 in early lens development has been well documented, its role in optic vesicle neuroepithelium and early retinal progenitors is poorly understood. Here we show that conditional inactivation of Pax6 at distinct time points of mouse neuroretina development has a different impact on early eye morphogenesis. When Pax6 is eliminated in the retina at E10.5 using an mRx-Cre transgene, after a sufficient contact between the optic vesicle and surface ectoderm has occurred, the lens develops normally but the pool of retinal progenitor cells gradually fails to expand. Furthermore, a normal differentiation program is not initiated, leading to almost complete disappearance of the retina after birth. By contrast, when Pax6 was inactivated at the onset of contact between the optic vesicle and surface ectoderm in Pax6Sey/flox embryos, expression of lens-specific genes was not initiated and neither the lens nor the retina formed. Our data show that Pax6 in the optic vesicle is important not only for proper retina development, but also for lens formation in a non-cell-autonomous manner. KEY WORDS: Pax6, Retinal progenitor, mRx-Cre, Lens induction INTRODUCTIONProper eye development is dependent on the coordinated formation of two main tissues in the eye: the retina and the lens. Vertebrate eye development begins with invagination of the optic vesicle (OV) toward the lens-competent head surface ectoderm (SE). As OV contacts SE, a series of reciprocal inductive signals elicit formation of the lens placode (LP) and subsequent invagination of both LP and OV to form a two-layered optic cup (OC), with retinal pigmented epithelium (RPE) surrounding the retina (reviewed by Fuhrmann, 2010; Chow and Lang, 2001;Ogino et al., 2012). Genetic studies have identified multiple transcription factors and signaling pathways interacting in a complex network orchestrating early eye development (reviewed by Fuhrmann, 2010; Chow and Lang, 2001;Ogino et al., 2012;Xie and Cvekl, 2011). Among the signaling pathways, BMP (Furuta and Hogan, 1998;Rajagopal et al., 2009;Sjödal et al., 2007;Wawersik et al., 1999) and FGF (Faber et al., 2001;Garcia et al., 2011;Gotoh et al., 2004;Pan et al., 2006) were found to be essential for lens induction and coordinated OV-to-OC transition, as severe eye defects are associated with their inactivation. RESEARCH ARTICLEInstitute of Molecular Genetics, Academy of Sciences of the Czech Republic, Videnska 1083, 14420 Prague 4, Czech Republic. At the time the LP is formed, the dorsal region of the OV becomes specified to the retina and is populated with mitotically active retinal progenitor cells (RPCs) (Fuhrmann, 2010;Levine and Green, 2004). Lineage-tracing studies have shown that RPCs a...

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Lens morphogenesis is dependent on Pax6‐mediated inhibition of the canonical Wnt/beta‐catenin signaling in the lens surface ectoderm

Cited by 54 publications

References 49 publications

Pax6-dependent, but β-catenin-independent, function of Bcl9 proteins in mouse lens development

Pax6-dependent, but β-catenin-independent, function of Bcl9 proteins in mouse lens development

The Dkk1 dose is critical for eye development

Stage-dependent requirement of neuroretinal Pax6 for lens and retina development

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