Explore the vast range of titles available.

The niche is a conserved regulator of stem cell quiescence and function. During ageing, stem cell function declines. To what extent and by what means age-related changes within the niche contribute to this phenomenon are unknown. Here we demonstrate that the aged muscle stem cell niche, the muscle fibre, expresses Fgf2 under homeostatic conditions, driving a subset of satellite cells to break quiescence and lose their self-renewing capacity. We show in mice that relatively dormant aged satellite cells robustly express sprouty 1 ( Spry1 ), an inhibitor of fibroblast growth factor (FGF) signalling. Increasing FGF signalling in aged satellite cells under homeostatic conditions by removing Spry1 results in the loss of quiescence, satellite cell depletion and diminished regenerative capacity. Conversely, reducing niche-derived FGF activity through inhibition of Fgfr1 signalling or overexpression of Spry1 in satellite cells prevents their depletion. These experiments identify an age-dependent change in the stem cell niche that directly influences stem cell quiescence and function. The expression of fibroblast growth factor in aged muscle fibre, the muscle stem cell niche, is shown to cause satellite cells to lose the capacity for self-renewal, and is thus an age-dependent change that directly influences stem cell quiescence and function. Stem-cell niche less stable with age The efficiency of stem-cell maintenance declines with age, but it is not clear whether the stem-cell niche itself plays a part in this decline. Here, Andrew Brack and colleagues report that as mice age, the skeletal-muscle niche becomes more mitogenic — meaning more cells undergo mitosis and differentiation — and less capable of maintaining the quiescence of the skeletal-muscle stem cells. This results in the loss of capacity for stem-cell self-renewal. The protein FGF2 is a key mitogenic factor in the aged niche, although a small number of muscle stem cells express SPRY1, an inhibitor of FGF signalling, and maintain some quiescence in aged skeletal-muscle fibres.

Cerebellar dysfunction has been demonstrated in autism spectrum disorders (ASDs); however, the circuits underlying cerebellar contributions to ASD-relevant behaviors remain unknown. In this study, we demonstrated functional connectivity between the cerebellum and the medial prefrontal cortex (mPFC) in mice; showed that the mPFC mediates cerebellum-regulated social and repetitive/inflexible behaviors; and showed disruptions in connectivity between these regions in multiple mouse models of ASD-linked genes and in individuals with ASD. We delineated a circuit from cerebellar cortical areas Right crus 1 (Rcrus1) and posterior vermis through the cerebellar nuclei and ventromedial thalamus and culminating in the mPFC. Modulation of this circuit induced social deficits and repetitive behaviors, whereas activation of Purkinje cells (PCs) in Rcrus1 and posterior vermis improved social preference impairments and repetitive/inflexible behaviors, respectively, in male PC-Tsc1 mutant mice. These data raise the possibility that these circuits might provide neuromodulatory targets for the treatment of ASD.Kelly et al. describe two cerebellum–thalamus–mPFC pathways in mice that regulate social and repetitive behavior. PC activation in Rcrus1 and posterior vermis improved social and reduced repetitive behaviors, respectively, in PC-Tsc1 mutant mice.

Jeremy Green and colleagues determine that the mechanism establishing the pattern of rugae on the embryonic vertebrate palate is an activator-inhibitor reaction-diffusion mechanism rather than an alternative pattern signaling system, such as lateral inhibition. We present direct evidence of an activator-inhibitor system in the generation of the regularly spaced transverse ridges of the palate. We show that new ridges, called rugae, that are marked by stripes of expression of Shh (encoding Sonic hedgehog), appear at two growth zones where the space between previously laid rugae increases. However, inter-rugal growth is not absolutely required: new stripes of Shh expression still appeared when growth was inhibited. Furthermore, when a ruga was excised, new Shh expression appeared not at the cut edge but as bifurcating stripes branching from the neighboring stripe of Shh expression, diagnostic of a Turing-type reaction-diffusion mechanism. Genetic and inhibitor experiments identified fibroblast growth factor (FGF) and Shh as components of an activator-inhibitor pair in this system. These findings demonstrate a reaction-diffusion mechanism that is likely to be widely relevant in vertebrate development.

Heterozygous mutation of chromodomain helicase DNA binding protein 8 (CHD8) is strongly associated with autism spectrum disorder (ASD) and results in dysregulated expression of neurodevelopmental and synaptic genes during brain development. To reveal how these changes affect ASD-associated cortical circuits, we studied synaptic transmission in the prefrontal cortex of a haploinsufficient Chd8 mouse model. We report profound alterations to both excitatory and inhibitory synaptic transmission onto deep layer projection neurons, resulting in a reduced excitatory:inhibitory balance, which were found to vary dynamically across neurodevelopment and result from distinct effects of reduced Chd8 expression within individual neuronal subtypes. These changes were associated with disrupted regulation of homeostatic plasticity mechanisms operating via spontaneous neurotransmission. These findings therefore directly implicate CHD8 mutation in the disruption of ASD-relevant circuits in the cortex.

Zinc and plant-derived ligands of the aryl hydrocarbon receptor (AHR) are dietary components affecting intestinal epithelial barrier function. Here, we explore whether zinc and the AHR pathway are linked. We show that dietary supplementation with an AHR pre-ligand offers protection against inflammatory bowel disease in a mouse model while protection fails in mice lacking AHR in the intestinal epithelium. AHR agonist treatment is also ineffective in mice fed zinc depleted diet. In human ileum organoids and Caco-2 cells, AHR activation increases total cellular zinc and cytosolic free Zn 2+ concentrations through transcription of genes for zinc importers. Tight junction proteins are upregulated through zinc inhibition of nuclear factor kappa-light-chain-enhancer and calpain activity. Our data show that AHR activation by plant-derived dietary ligands improves gut barrier function at least partly via zinc-dependent cellular pathways, suggesting that combined dietary supplementation with AHR ligands and zinc might be effective in preventing inflammatory gut disorders. Dietary zinc and plant-derived aryl hydrocarbon receptor (AHR) agonists are involved in maintaining intestinal epithelium integrity. The authors show that combined supplementation with AHR ligands and zinc might be effective in preventing inflammatory gut disorders.

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a persistent and toxic environmental pollutant. Gestational exposure to TCDD has been linked to cognitive and motor deficits, and increased incidence of autism spectrum disorder (ASD) traits in children. Most animal studies of these neurodevelopmental effects involve acute TCDD exposure, which does not model typical exposure in humans.

Deregulation of chromatin modifiers plays an essential role in the pathogenesis of medulloblastoma, the most common paediatric malignant brain tumour. Here, we identify a BMI1-dependent sensitivity to deregulation of inositol metabolism in a proportion of medulloblastoma. We demonstrate mTOR pathway activation and metabolic adaptation specifically in medulloblastoma of the molecular subgroup G4 characterised by a BMI1 High ;CHD7 Low signature and show this can be counteracted by IP6 treatment. Finally, we demonstrate that IP6 synergises with cisplatin to enhance its cytotoxicity in vitro and extends survival in a pre-clinical BMI1 High ;CHD7 Low xenograft model. BMI1 and CHD7 are chromatin remodelling genes with a role in medulloblastoma pathogenesis. Here, the authors demonstrate that the BMI1 High /CHD7 Low signature mediates metabolic adaptation in G4 MB and predicts response to inositol treatment either alone or in combination with chemotherapy.

A study has found that young male mice with a mutation of the autism-associated gene Chd8 show abnormal behaviors and elevated neuronal activation in several brain areas under stressful conditions, while female mice with the same mutation have reduced baseline neuronal activity, which may protect them from developing these abnormal phenotypes.

Neurons and sensory cells are particularly vulnerable to oxidative stress due to their high oxygen demand during stimulus perception and transmission. The mechanisms that protect them from stress-induced death and degeneration remain elusive. Here we show that embryonic deletion of the chromodomain helicase DNA-binding protein 7 (CHD7) in auditory neurons or hair cells leads to sensorineural hearing loss due to postnatal degeneration of both cell types. Mechanistically, we demonstrate that CHD7 controls the expression of major stress pathway components. In its absence, hair cells are hypersensitive, dying rapidly after brief exposure to stress inducers, suggesting that sound at the onset of hearing triggers their degeneration. In humans, CHD7 haploinsufficiency causes CHARGE syndrome, a disorder affecting multiple organs including the ear. Our findings suggest that CHD7 mutations cause developmentally silent phenotypes that predispose cells to postnatal degeneration due to a failure of protective mechanisms.To improve our understanding of the mechanisms that protect hair cells in the ear from stress-induced death, Ahmed et al delete the chromodomain helicase DNA-binding protein 7 (CHD7) in auditory neurons and hair cells in mice. They observe sensorineural hearing loss and demonstrate that CHD7 controls the expression of stress pathway components, which could help to explain how CHD7 haploinsufficiency causes changes in the ear associated with CHARGE syndrome.

Over the last 60 years, the spotlight of research has periodically returned to the cerebellum as new techniques and insights have emerged. Because of its simple homogeneous structure, limited diversity of cell types and characteristic behavioral pathologies, the cerebellum is a natural home for studies of cell specification, patterning, and neuronal migration. However, recent evidence has extended the traditional range of perceived cerebellar function to include modulation of cognitive processes and implicated cerebellar hypoplasia and Purkinje neuron hypo-cellularity with autistic spectrum disorder. In the light of this emerging frontier, we review the key stages and genetic mechanisms behind cerebellum development. In particular, we discuss the role of the midbrain hindbrain isthmic organizer in the development of the cerebellar vermis and the specification and differentiation of Purkinje cells and granule neurons. These developmental processes are then considered in relation to recent insights into selected human developmental cerebellar defects: Joubert syndrome, Dandy-Walker malformation, and pontocerebellar hypoplasia. Finally, we review current research that opens up the possibility of using the mouse as a genetic model to study the role of the cerebellum in cognitive function.