Abstract
ObjectiveUpregulation of the RNA-binding protein Musashi-1 (Msi1) has been shown to occur in rat gastric corpus mucosa after ethanol-induced mucosal injury. However, there is no direct evidence linking Msi1 with gastric regeneration. We examined the process of tissue repair after acute gastric mucosal injury with Msi1-knock-out (KO) mice to clarify the role of Msi1 and Msi1-dependent regulation of m-Numb expression in regenerating gastric mucosa.MethodsAcute gastric injury was induced in Msi1-KO and wild-type ICR mice by administering absolute ethanol. Expression of the splicing variants of m-Numb mRNA and protein in the gastric mucosa were analyzed by quantitative RT-PCR and western blotting, respectively.ResultsWe demonstrated that phosphotyrosine-binding domain-containing m-Numb expression was significantly upregulated at both the mRNA and protein levels in wild-type mice at 3 h after ethanol-induced acute gastric injury. In contrast, in Msi1-KO mice, the m-Numb protein was expressed weakly, and was associated with delayed regeneration of the injured gastric mucosal epithelium. In the Msi1-KO mouse, the ratio of m-Numb mRNA to total m-Numb mRNA in the heavy polysome fractions was lower than that in the wild-type mouse. Further, we showed that m-Numb-enhancement in gastric mucous cells induced the expression of prostate stem cell antigen and metallothionein-2. Under the m-Numb enhancing condition, the gastric cells exhibited enhanced cell proliferation and were significantly more resistant to H2O2-induced cell death than control cells.ConclusionsMsi1-dependent post-transcriptional enhancement of m-Numb is crucial in gastric epithelial regeneration.
Highlights
Epithelia in the digestive tract exhibit a remarkable capacity for regeneration
We demonstrate that splicing variantspecific m-Numb expression is induced during gastric mucosal regeneration after acute damage, and that the stomachs of Msi1knock-out (Msi1-KO) mice, which lack the m-Numb expression response, show delayed gastric regeneration
We firstly examined the histochemical analysis of gastric mucosa of wild-type and Msi1-KO mice in the water-treated control group
Summary
Epithelia in the digestive tract exhibit a remarkable capacity for regeneration. Gastric mucosal architecture is restored within a very short period following injury [1,2,3]. The mechanisms underlying this rapid restoration of the gastric mucosal architecture have not yet been fully clarified. An RNA-binding protein, Musashi-1 (Msi1) [4,5,6] was isolated as a mammalian homologue of the Drosophila Musashi; this protein is required for the asymmetric cell division of the sensory neural precursor cells [7,8]. In the mammalian central nervous system, Msi is known to regulate progenitor cell function through the post-transcriptional regulation of its target RNA [4,5,6]. There is no direct evidence linking Msi with gastric regeneration
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