Mutations in LRP5 or FZD4 Underlie the Common Familial Exudative Vitreoretinopathy Locus on Chromosome 11q

Toomes, Carmel; Bottomley, H.M.; Jackson, Richard M.; Towns, Katherine V.; Scott, Simon; Mackey, David A.; Craig, Jamie E; Jiang, Li; Yang, Zhenglin; Trembath, Richard C.; Woodruff, Geoffrey; Gregory‐Evans, Cheryl Y.; Gregory-Evans, Kevin; Parker, Michael; Black, Graeme C M; Downey, Louise; Zhang, Kang; Inglehearn, Chris F.

doi:10.1086/383202

Cited by 323 publications

(247 citation statements)

References 46 publications

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“…The first direct evidence of the involvement of Wnt signaling in diseases of the retina came from the identification of inactivating point mutations and deletions in the Wnt coreceptors Frizzled4 (Fz4) (21) and LRP5 (22) that are associated with autosomal dominant familial exudative vitreoretinopathy (FEVR), a blinding disease characterized by a disruption of the retinal vascular system. Currently, nearly a dozen causative mutations in Fz4 and LRP5 are linked to FEVR; because these mutations only account for a minority of cases it is possible that other genes in the Wnt pathway will be implicated.…”

Section: Alteration Of Wnt Pathway Components In Retinal Diseasementioning

confidence: 99%

The Wnt Signaling Pathway in Retinal Degenerations

Hackam

2005

IUBMB Life (International Union of Biochemistry and Molecular B

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The retina is a complex tissue composed of multiple interconnected cell layers, highly specialized for transforming light and color into electrical signals perceived by the brain. Damage or death of the primary light‐sensing cells, the photoreceptors, results in devastating effects on vision. Despite the identification of numerous mutations that cause inherited retinal degenerations, the cellular and molecular mechanisms leading from the primary mutations to photoreceptor apoptosis are not understood. Wnt signaling has essential regulatory functions in a wide variety of critical developmental processes. Our research and others' have suggested that the Wnt pathway may be involved in retinal degeneration. Wnt ligands regulate developmental death of Drosophila photoreceptors, dysregulated Wnt signaling is involved in neuronal degeneration elsewhere in the central nervous system and Wnts control the expression of pro‐survival growth factors in mammalian tissues. Additionally, altered expression of Wnt pathway genes, including the anti‐apoptotic Wnt signaling regulator Dickkopf 3 (Dkk3), were observed during photoreceptor loss. This review examines the evidence and develops a model proposing a pro‐survival role for Wnt signaling during photoreceptor injury. Because manipulating Wnt signaling has been demonstrated to have therapeutic potential for the treatment of Alzheimers disease, understanding the involvement of Wnts in photoreceptor death will determine whether targeting the Wnt pathway should also be considered as a possible therapeutic strategy for retinal degenerations. IUBMB Life, 57: 381‐388, 2005

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Section: Alteration Of Wnt Pathway Components In Retinal Diseasementioning

confidence: 99%

The Wnt Signaling Pathway in Retinal Degenerations

Hackam

2005

IUBMB Life (International Union of Biochemistry and Molecular B

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“…3 Although the genetic causes of FEVR are still being intensively studied, to date the most common deficiencies are in genes encoding either receptors or ligand involved in the Wnt signaling pathway, including a Wnt receptor Frizzled4, the coreceptors low-density lipoprotein receptor-related protein 5 (LRP5) and tetraspanin 12 (TSPAN12), 4 and Wnt signaling ligand Norrin. 5,6 Wnt signaling is an important regulatory pathway in embryonic development and diseases. Proper Wnt signaling activation is required for vascular development 7 and plays a key role in numerous ocular diseases.…”

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confidence: 99%

Pharmacologic Activation of Wnt Signaling by Lithium Normalizes Retinal Vasculature in a Murine Model of Familial Exudative Vitreoretinopathy

Wang

Liu

Sun

et al. 2016

The American Journal of Pathology

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“…Some studies suggest that FZD4 signals through an alternative (Ca 21 ) Wnt pathway (Robitaille et al 2002). However, the finding that the mutations in the Wnt coreceptor LRP ( Jiao et al 2004;Toomes et al 2004a), which is implicated in Arm/b-catenin signaling and not in the Ca 21 pathway, also cause FEVR does not support this model. Moreover, FZD4 in collaboration with LRP5 can be stimulated to activate Arm/b-catenin signaling by Norrin, a non-Wnt ligand that binds to the CRD (Xu et al 2004).…”

Section: Discussionmentioning

confidence: 99%

Genetic Evidence That Drosophila frizzled Controls Planar Cell Polarity and Armadillo Signaling by a Common Mechanism

et al. 2005

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The frizzled ( fz) gene in Drosophila controls two distinct signaling pathways: it directs the planar cell polarization (PCP) of epithelia and it regulates cell fate decisions through Armadillo (Arm) by acting as a receptor for the Wnt protein Wingless (Wg). With the exception of dishevelled (dsh), the genes functioning in these two pathways are distinct. We have taken a genetic approach, based on a series of new and existing fz alleles, for identifying individual amino acids required for PCP or Arm signaling. For each allele, we have attempted to quantify the strength of signaling by phenotypic measurements. For PCP signaling, the defect was measured by counting the number of cells secreting multiple hairs in the wing. We then examined each allele for its ability to participate in Arm signaling by the rescue of fz mutant embryos with maternally provided fz function. For both PCP and Arm signaling we observed a broad range of phenotypes, but for every allele there is a strong correlation between its phenotypic strength in each pathway. Therefore, even though the PCP and Arm signaling pathways are genetically distinct, the set of signalingdefective fz alleles affected both pathways to a similar extent. This suggests that fz controls these two different signaling activities by a common mechanism. In addition, this screen yielded a set of missense mutations that identify amino acids specifically required for fz signaling function.A NIMAL development requires the interplay between cell fate decisions and morphogenetic events. It is not well understood how cell fate decisions, which are the outcome of changes in gene regulation, are coordinated with changes in morphology, such as cell movement, shape change, and polarization. The frizzled ( fz) gene in Drosophila has the remarkable ability to control both cell fate decisions and the planar polarization of epithelia. What makes fz exceptional is that it interacts with two distinct signaling cascades to accomplish these functions. We are trying to understand the mechanism that regulates the switch between these two pathways. Uncovering how fz chooses between these two functions will provide insight into how morphogenesis and cell fate choices are orchestrated.

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Mutations in LRP5 or FZD4 Underlie the Common Familial Exudative Vitreoretinopathy Locus on Chromosome 11q

Cited by 323 publications

References 46 publications

The Wnt Signaling Pathway in Retinal Degenerations

The Wnt Signaling Pathway in Retinal Degenerations

Pharmacologic Activation of Wnt Signaling by Lithium Normalizes Retinal Vasculature in a Murine Model of Familial Exudative Vitreoretinopathy

Genetic Evidence That Drosophila frizzled Controls Planar Cell Polarity and Armadillo Signaling by a Common Mechanism

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