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Sprouty2-modulated Kras signaling rescues Shp2 deficiency during lens and lacrimal gland development.

ABSTRACT: Shp2/Ptpn11 tyrosine phosphatase is a general regulator of the RTK pathways. By genetic ablation, we demonstrate that Shp2 is required for lacrimal gland budding, lens cell proliferation, survival and differentiation. Shp2 deletion disrupted ERK signaling and cell cycle regulation, which could be partially compensated by activated Kras signaling, confirming that Ras signaling was the main downstream target of Shp2 in lens and lacrimal gland development. We also showed that Sprouty2, a general suppressor of Ras signaling, was regulated by Shp2 positively at the transcriptional level and negatively at the post-translational level. Only in the absence of Sprouty2 could activated Kras signaling robustly rescue the lens proliferation and lacrimal-gland-budding defects in the Shp2 mutants. We propose that the dynamic regulation of Sprouty by Shp2 might be important not only for modulating Ras signaling in lens and lacrimal gland development, but also for RTK signaling in general.

SUBMITTER: Pan Y

PROVIDER: S-EPMC2835324 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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Sprouty2-modulated Kras signaling rescues Shp2 deficiency during lens and lacrimal gland development.

Pan Yi Y Carbe Christian C Powers Andrea A Feng Gen-Sheng GS Zhang Xin X

Development (Cambridge, England) 20100401 7

Shp2/Ptpn11 tyrosine phosphatase is a general regulator of the RTK pathways. By genetic ablation, we demonstrate that Shp2 is required for lacrimal gland budding, lens cell proliferation, survival and differentiation. Shp2 deletion disrupted ERK signaling and cell cycle regulation, which could be partially compensated by activated Kras signaling, confirming that Ras signaling was the main downstream target of Shp2 in lens and lacrimal gland development. We also showed that Sprouty2, a general su ...[more]

PMID: 20215346

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Project description:BackgroundAqueous-deficient dry eye disease (ADDED) resulting from dysfunction of the lacrimal gland (LG) is currently incurable. Although LG stem/progenitor cell-based therapy is considered to be a promising strategy for ADDED patients, the lack of a reliable serum-free culture method to obtain enough lacrimal gland stem cells (LGSCs) and the basic standard of LGSC transplantation are obstacles for further research.MethodsAdult mouse LGSCs were cultured in Matrigel-based 3D culture under serum-free culture condition, which contained EGF, FGF10, Wnt3A, and Y-27632. LGSCs were continuously passaged over 40 times every 7 days, and the morphology and cell numbers were recorded. LGSCs were induced to differentiate to ductal cells by reducing Matrigel rigidity, while fetal bovine serum was used for the induction of acinar cells. RT-PCR or qRT-PCR analysis, RNA-sequence analysis, H&E staining, and immunofluorescence were used for characterization and examining the differentiation of LGSCs. LGSCs were allotransplanted into diseased LGs to examine the ability of repairing the damage. The condition of eye orbits was recorded using a camera, the tear production was measured using phenol red-impregnated cotton threads, and the engraftments of LGSCs were examined by immunohistochemistry.ResultsWe established an efficient 3D serum-free culture for adult mouse LGSCs, in which LGSCs could be continuously passaged for long-term expansion. LGSCs cultured from both the healthy and ADDED mouse LGs expressed stem/progenitor cell markers Krt14, Krt5, P63, and nestin, had the potential to differentiate into acinar or ductal-like cells in vitro and could engraft into diseased LGs and relieve symptoms of ADDED after orthotopic injection of LGSCs.ConclusionWe successfully established an efficient serum-free culture for adult mouse LGSCs aiming at LG repair for the first time. Our approach provides an excellent theoretical and technical reference for future clinical research for ADDED stem cell therapy.

Dataset Information

Sprouty2-modulated Kras signaling rescues Shp2 deficiency during lens and lacrimal gland development.

Publications

Sprouty2-modulated Kras signaling rescues Shp2 deficiency during lens and lacrimal gland development.

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