Mouse knockout of guanylyl cyclase C: Recognition memory deficits in the absence of activity changes

Guanylyl cyclase C (GC‐C) is found in brain regions where dopamine is expressed. We characterized a mouse in which GC‐C was knocked out (KO) that was reported to be a model of attention deficit hyperactivity disorder (ADHD). We re‐examined this model and controlled for litter effects, used 16 to 23 mice per genotype per sex and assessed an array of behavioral and neurochemical outcomes. GC‐C KO mice showed no phenotypic differences from wild‐type mice on most behavioral tests, or on striatal or hippocampal monoamines, and notably no evidence of an ADHD‐like phenotype. KO mice were impaired on novel object recognition, had decreased tactile startle but not acoustic startle, and females had increased latency on cued training trials in the Morris water maze, but not hidden platform spatial learning trials. Open‐field activity showed small differences in females but not males. The data indicate that the GC‐C KO mouse with proper controls and sample sizes has a moderate cognitive and startle phenotype but has no ADHD‐like phenotype.     

Changes throughout a Genetic Network Mask the Contribution of Hox Gene Evolution

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A novel indirubin derivative that increases somatic cell plasticity and inhibits tumorigenicity

Indirubin-based compounds affect diverse biological processes, such as inflammation and angiogenesis. In this study, we tested a novel indirubin derivative, LDD-1819 (2-((((2Z,3E)-5-hydroxy-5′-nitro-2′-oxo-[2,3′-biindolinylidene]-3-ylidene)amino)oxy)ethan-1-aminium chloride) for two major biological activities: cell plasticity and anti-cancer activity. Biological assays indicated that LDD-1819 induced somatic cell plasticity. LDD-1819 potentiated myoblast reprogramming into osteogenic cells and fibroblast reprogramming into adipogenic cells. Interestingly, in an assay of skeletal muscle dedifferentiation, LDD-1819 induced human muscle cellularization and blocked residual proliferative activity to produce a population of mononuclear refractory cells, which is also observed in the early stages of limb regeneration in urodele amphibians. In cancer cell lines, LDD-1819 treatment inhibited cell invasion and selectively induced apoptosis compared to normal cells. In an animal tumor xenograft model, LDD-1819 reduced human cancer cell metastasis in vivo at doses that did not produce toxicity. Biochemical assays showed that LDD-1819 possessed inhibitory activity against glycogen synthase kinase-3β, which is linked to cell plasticity, and aurora kinase, which regulates carcinogenesis. These results indicate that novel indirubin derivative LDD-1819 is a dual inhibitor of glycogen synthase kinase-3β and aurora A kinase, and has potential for development as an anti-cancer drug or as a reprogramming agent for cell-therapy based approaches to treat degenerative diseases.     

A Ubiquitin-Binding Domain that Binds a Structural Fold Distinct from that of Ubiquitin

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