Sprouty2 regulates positioning of retinal progenitors through suppressing the Ras/Raf/MAPK pathway
Jian Sun1, Jaeho Yoon1, Moonsup Lee1
1Cancer and Developmental Biology Laboratory, National Cancer Institute, Frederick, MD, 21702, USA.
Abstract:
Sproutys are negative regulators of the Ras/Raf/MAPK signaling pathway and involved in regulation of organogenesis, differentiation, cell migration and proliferation. Although the function of Sproutys have been extensively studied during embryonic development, their role and mode of action during eye formation in vertebrate embryonic development is still unknown. Here we show that Xenopus sprouty2 is expressed in the optic vesicle at late neurula stage and knockdown of Sprouty2 prevents retinal progenitors from populating the retina, which in turn gives rise to small eyes. In the absence of Sprouty2, progenitor cell population of the retina can be restored by blocking the MAPK signaling pathway through overexpression of DN-Ras or DN-Raf. In contrast, activation of the MAPK pathway through overexpression of a constitutively active form of c-Raf (ca-Raf) inhibits progenitor population of the retina, similar to the Sprouty2 loss-of-function phenotype. Moreover, we present evidence that the retinal defect observed in Sprouty2 morphants is attributed to the failure of proper movement of retinal progenitors into the optic vesicle, rather than an effect on progenitor cell survival. These results suggest that Sprouty2 is required for the positioning of retinal progenitors within the optic vesicle through suppressing Ras/Raf/MAPK signaling pathway.
Insights
Sprouty2 is crucial for vertebrate eye development by regulating retinal progenitor cell positioning. Suppressing the Ras/Raf/MAPK pathway ensures proper eye formation.
Area of Science:
- Developmental Biology
- Molecular Biology
- Cell Biology
Background:
- Sproutys negatively regulate the Ras/Raf/MAPK pathway, impacting organogenesis and cell behavior.
- The specific role of Sproutys in vertebrate embryonic eye formation remains largely uncharacterized.
Purpose of the Study:
- To investigate the function and mechanism of Xenopus sprouty2 during embryonic eye development.
- To determine if Sprouty2 influences retinal progenitor cell population and positioning.
Main Methods:
- Xenopus sprouty2 expression analysis in optic vesicles.
- Knockdown of Sprouty2 using morpholinos.
- Manipulation of the MAPK pathway via overexpression of dominant-negative Ras/Raf or constitutively active Raf.
Main Results:
- Sprouty2 is expressed in the optic vesicle and its knockdown leads to small eyes due to reduced retinal progenitor cell population.
- MAPK pathway inhibition rescues the small eye phenotype in Sprouty2 knockdown embryos.
- MAPK pathway activation mimics the Sprouty2 loss-of-function phenotype, impairing retinal progenitor cell population.
- Retinal defects result from impaired progenitor cell migration, not altered survival.
Conclusions:
- Sprouty2 is essential for positioning retinal progenitor cells within the optic vesicle during vertebrate eye development.
- Sprouty2 functions by suppressing the Ras/Raf/MAPK signaling pathway to control progenitor cell migration.
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