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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by chronic progressive degeneration of motor neurons resulting in muscular atrophy, paralysis, and ultimately death. We have investigated the expression of Wnt1 and Fzd1 in the spinal cords of SOD1G93A ALS transgenic mice, SOD1G93A-transfected N2a cells, and primary cultured astrocytes from SOD1G93A transgenic mice. In addition, we provided further insight into the role of Wnt1 and Fzd1 in the pathogenesis of ALS transgenic mice and discuss the mechanisms underlying the Wnt signal pathway which may be useful in the treatment of ALS. The results indicate the involvement of Wnt1 and Fzd1 in the pathogenesis and development of ALS.

a b s t r a c tSpina bifida is a complex congenital malformation resulting from failure of fusion in the spinal neural tube during embryogenesis. However, the cellular mechanism underlying spina bifida is not fully understood.Here, we investigated cell apoptosis in whole embryos and proliferation of neural progenitor cells in the spinal neural tube during neurulation in all-trans retinoic acid (atRA)-induced spina bifida in fetal rats. Cell apoptosis was assessed by TUNEL assay on whole-mount and serially sectioned samples of rat embryos with spina bifida. Cell proliferation of lumbo-sacral neural progenitor cells was assessed by staining for the mitotic marker Ki67 and pH3. We found an excess of apoptosis in the neuroepithelium of embryos with spina bifida, which became more marked as embryos progress from E11 to E13. Conversely, there was a reduction in cell proliferation in spina bifida embryos, with a progressively greater difference from controls with stage from E11 to 13. Thus, atRA-induced spina bifida in rat shows perturbed apoptosis and proliferation of neural progenitors in the lumbo-sacral spinal cord during embryonic development, which might contribute to the pathogenesis of spina bifida.

No abstract

The intestinal mucosal barrier is critical for host defense against pathogens infection. Here, we demonstrate that the mixed lineage kinase-like protein (MLKL), a necroptosis effector, promotes intestinal epithelial barrier function by enhancing inflammasome activation. MLKL−/− mice were more susceptible to Salmonella infection compared with wild-type counterparts, with higher mortality rates, increased body weight loss, exacerbated intestinal inflammation, more bacterial colonization, and severe epithelial barrier disruption. MLKL deficiency promoted early epithelial colonization of Salmonella prior to developing apparent intestinal pathology. Active MLKL was predominantly expressed in crypt epithelial cells, and experiments using bone marrow chimeras found that the protective effects of MLKL were dependent on its expression in non-hematopoietic cells. Intestinal mucosa of MLKL−/− mice had impaired caspase-1 and gasdermin D cleavages and decreased interleukin (IL)-18 release. Moreover, administration of exogenous recombinant IL-18 rescued the phenotype of increased bacterial colonization in MLKL−/− mice. Thus, our results uncover the role of MLKL in enhancing inflammasome activation in intestinal epithelial cells to inhibit early bacterial colonization.