Regulation of retinal progenitor expansion by Frizzled receptors: implications for microphthalmia and retinal coloboma
| Autor: | Anand Swaroop, Tiansen Li, Chunqiao Liu, Hirva Bakeri |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
rho GTP-Binding Proteins
Frizzled Neurogenesis Optic Disk Optic disk Down-Regulation Mitosis Biology Microphthalmia Retina Receptors G-Protein-Coupled chemistry.chemical_compound Mice Neural Stem Cells Genetics medicine Animals Microphthalmos Gliosis Molecular Biology Genetics (clinical) beta Catenin Mice Knockout Coloboma Wnt signaling pathway Gene Expression Regulation Developmental Retinal General Medicine Articles medicine.disease Axons Frizzled Receptors Cell biology medicine.anatomical_structure chemistry Mutation Retinal Defect rhoA GTP-Binding Protein Retinal Neurons Signal Transduction |
| Zdroj: | Human molecular genetics. 21(8) |
| ISSN: | 1460-2083 |
| Popis: | Nineteen Wnt ligands and 10 Frizzled (Fz) receptors mediate multiple distinct cellular events during neuronal development. However, their precise roles in cell-type specification and organogenesis are poorly delineated because of overlapping functions and expression profiles. Here, we have explored the role of two closely related Frizzled receptors, Fz5 and Fz8, in mouse retinal development. We previously showed that Fz5(-/-) mice exhibit mild coloboma and microphthalmia at ~50% penetrance. Fz8 expression overlaps with Fz5 in the neural retina and optic fissure/disc. Mice lacking Fz8 show minimal eye and retinal defects. The embryos lacking both Fz5 and Fz8 die early in development, but a majority of triallelic Fz5(-/-);Fz8(+/-) mutants survive until birth. The triallelic mutant develops severe retinal coloboma and microphthalmia with full penetrance. At the cellular level, impaired neurogenesis is indicated by increased early-born retinal neurons that result from accelerated cell cycle exit of progenitors. Deficiency of apical retinal neuroepithelium is indicated by altered localization of apical junction markers, such as atypical protein kinase C, RhoA and β-catenin. Hes1 expression, which is critical for retinal progenitor expansion, is down-regulated in the triallelic mutant mouse. Furthermore, blocking Frizzled receptors in cultured retinal explants led to basally shifted divisions of retinal progenitors. Together, our studies suggest a dose-dependent regulation of signaling by Fz5 and Fz8 in optic fissure/disc formation and progenitor expansion. |
| Databáze: | OpenAIRE |
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