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Williams-Beuren syndrome (WBS) is a rare disorder caused by hemizygous microdeletion of ∼27 contiguous genes. Despite neurodevelopmental and cognitive deficits, individuals with WBS have spared or enhanced musical and auditory abilities, potentially offering an insight into the genetic basis of auditory perception. Here, we report that the mouse models of WBS have innately enhanced frequency-discrimination acuity and improved frequency coding in the auditory cortex (ACx). Chemogenetic rescue showed frequency-discrimination hyperacuity is caused by hyperexcitable interneurons in the ACx. Haploinsufficiency of one WBS gene, Gtf2ird1, replicated WBS phenotypes by downregulating the neuropeptide receptor VIPR1. VIPR1 is reduced in the ACx of individuals with WBS and in the cerebral organoids derived from human induced pluripotent stem cells with the WBS microdeletion. Vipr1 deletion or overexpression in ACx interneurons mimicked or reversed, respectively, the cellular and behavioral phenotypes of WBS mice. Thus, the Gtf2ird1-Vipr1 mechanism in ACx interneurons may underlie the superior auditory acuity in WBS.

Prader-Willi syndrome (PWS) is a developmental disorder caused by loss of maternally imprinted genes on 15q11-q13, including melanoma antigen gene family member L2 (MAGEL2). The clinical phenotypes of PWS suggest impaired hypothalamic neuroendocrine function; however, the exact cellular defects are unknown. Here, we report deficits in secretory granule (SG) abundance and bioactive neuropeptide production upon loss of MAGEL2 in humans and mice. Unbiased proteomic analysis of Magel2pΔ/m+ mice revealed a reduction in components of SG in the hypothalamus that was confirmed in 2 PWS patient–derived neuronal cell models. Mechanistically, we show that proper endosomal trafficking by the MAGEL2-regulated WASH complex is required to prevent aberrant lysosomal degradation of SG proteins and reduction of mature SG abundance. Importantly, loss of MAGEL2 in mice, NGN2-induced neurons, and human patients led to reduced neuropeptide production. Thus, MAGEL2 plays an important role in hypothalamic neuroendocrine function, and cellular defects in this pathway may contribute to PWS disease etiology. Moreover, these findings suggest unanticipated approaches for therapeutic intervention., Prader-Willi Syndrome arises in part through loss of MAGEL2-regulated secretory granule biogenesis and neuropeptide production in the hypothalamus.

SUMMARYStress granules (SG) are membrane-less ribonucleoprotein condensates that form in response to various stress stimuli via phase separation. SG act as a protective mechanism to cope with acute stress, but persistent SG have cytotoxic effects that are associated with several age-related diseases. Here, we demonstrate that the testis-specific protein, MAGE-B2, increases cellular stress tolerance by suppressing SG formation through translational inhibition of the key SG nucleator G3BP. MAGE-B2 reduces G3BP protein levels below the critical concentration for phase separation and suppresses SG initiation. Importantly, knockout of the MAGE-B2 mouse ortholog confers hypersensitivity of the male germline to heat stress in vivo. Thus, MAGE-B2 provides cytoprotection to maintain mammalian spermatogenesis, a highly thermo-sensitive process that must be preserved throughout reproductive life. These results demonstrate a mechanism that allows for tissue-specific resistance against stress through fine-tuning phase separation and could aid in the development of male fertility therapies.

Summary Stress granules (SGs) are membrane-less ribonucleoprotein condensates that form in response to various stress stimuli via phase separation. SGs act as a protective mechanism to cope with acute stress, but persistent SGs have cytotoxic effects that are associated with several age-related diseases. Here, we demonstrate that the testis-specific protein, MAGE-B2, increases cellular stress tolerance by suppressing SG formation through translational inhibition of the key SG nucleator G3BP. MAGE-B2 reduces G3BP protein levels below the critical concentration for phase separation and suppresses SG initiation. Knockout of the MAGE-B2 mouse ortholog or overexpression of G3BP1 confers hypersensitivity of the male germline to heat stress in vivo. Thus, MAGE-B2 provides cytoprotection to maintain mammalian spermatogenesis, a highly thermosensitive process that must be preserved throughout reproductive life. These results demonstrate a mechanism that allows for tissue-specific resistance against stress and could aid in the development of male fertility therapies.

Mammals evolved testis-specific Mage-a genes to protect the male germline under starvation stress and are co-opted in cancer., Ensuring robust gamete production even in the face of environmental stress is of utmost importance for species survival, especially in mammals that have low reproductive rates. Here, we describe a family of genes called melanoma antigens (MAGEs) that evolved in eutherian mammals and are normally restricted to expression in the testis (http://MAGE.stjude.org) but are often aberrantly activated in cancer. Depletion of Mage-a genes disrupts spermatogonial stem cell maintenance and impairs repopulation efficiency in vivo. Exposure of Mage-a knockout mice to genotoxic stress or long-term starvation that mimics famine in nature causes defects in spermatogenesis, decreased testis weights, diminished sperm production, and reduced fertility. Last, human MAGE-As are activated in many cancers where they promote fuel switching and growth of cells. These results suggest that mammalian-specific MAGE genes have evolved to protect the male germline against environmental stress, ensure reproductive success under non-optimal conditions, and are hijacked by cancer cells.

Routine health assessment of laboratory rodents can be improved using automated home cage monitoring. Continuous, non-stressful, objective assessment of rodents unaware that they are being watched, including during their active dark period, reveals behavioural and physiological changes otherwise invisible to human caretakers. We developed an automated feeder that tracks feed intake, body weight, and physical appearance of individual radio frequency identification-tagged mice in social home cages. Here, we experimentally induce illness via lipopolysaccharide challenge and show that this automated tracking apparatus reveals sickness behaviour (reduced food intake) as early as 2–4 hours after lipopolysaccharide injection, whereas human observers conducting routine health checks fail to detect a significant difference between sick mice and saline-injected controls. Continuous automated monitoring additionally reveals pronounced circadian rhythms in both feed intake and body weight. Automated home cage monitoring is a non-invasive, reliable mode of health surveillance allowing caretakers to more efficiently detect and respond to early signs of illness in laboratory rodent populations.

Drosophila melanogaster Piwi functions within the germline stem cells (GSCs) and the somatic niche to regulate GSC self-renewal and differentiation. How Piwi influences GSCs is largely unknown. We uncovered a genetic interaction between Piwi and c-Fos in the somatic niche that influences GSCs. c-Fos is a proto-oncogene that influences many cell and developmental processes. In wild-type ovarian cells, c-Fos is post-transcriptionally repressed by Piwi, which destabilized the c-Fos mRNA by promoting the processing of its 3′ untranslated region (UTR) into Piwi-interacting RNAs (piRNAs). The c-Fos 3′ UTR was sufficient to trigger Piwi-dependent destabilization of a GFP reporter. Piwi represses c-Fos in the somatic niche to regulate GSC maintenance and differentiation and in the somatic follicle cells to affect somatic cell disorganization, tissue dysmorphogenesis, oocyte maturation arrest, and infertility., Author Summary The Drosophila melanogaster ovary is consisted of germ cells differentiated from GSCs and ovarian somatic cells that provide structural support to the organ. Piwi is a ribonucleoprotein required for GSC maintenance and differentiation in the Drosophila ovary. Piwi does so by influencing GSC-autonomous mechanisms or the somatic niche signaling. The somatic niche is composed of cells adjacent to the GSC that signal to promote GSC functions. Piwi and piRNAs are also known to repress transposons. We found that Piwi genetically interacts with c-Fos in the somatic niche and represses c-Fos expression in the ovarian somatic cells. Piwi destabilizes the c-Fos mRNA by mediating the generation of piRNAs from its 3′ UTR. Piwi represses c-Fos in the somatic niche to promote GSC functions and in the somatic ovarian cells to influence cell organization, tissue morphogenesis, and egg production.

Dietary etiologies or treatments for complex mental disorder are highly controversial in psychiatry. Nevertheless, diet affects brain chemistry (particularly serotonin), and can reduce abnormal behavior in humans and animals. We formulated a diet that elevated brain serotonin and tested whether it would reduce hair pulling in a mouse model of trichotillomania. In a double-blind crossover trial, dietary elevation of brain serotonin unexpectedly increased hair pulling (P = 0.0006) and induced ulcerative dermatitis (UD; P = 0.001). The causative agent for UD is unknown. Therefore, we fed the treatment diet to a second group of mice to test whether UD is behavioral in origin. The diet increased scratching behavior (P < 0.0001). However, high scratching behavior (P = 0.027) and low barbering (P = 0.040) prior to treatment predicted the development of UD. Thus diet can trigger the onset of a complex disorder in the absence of an underlying metabolic deficit. Furthermore, we propose UD as model of compulsive skin-picking.

Research is uncovering the genetic and biochemical effects of consuming large quantities of alcohol. One prime example is the J- or U-shaped relationship between the levels of alcohol consumption and the risk of atherosclerotic cardiovascular disease. Moderate alcohol consumption in humans (about 30 g ethanol/d) is associated with reduced risk of coronary heart disease, while abstinence and heavier alcohol intake is linked to increased risk. However, the hepatic consequences of moderate alcohol drinking are largely unknown. Previous data from alcohol-preferring (P) rats showed that chronic consumption does not produce significant hepatic steatosis in this well-established model. Therefore, free-choice alcohol drinking in P rats may mimic low risk or nonhazardous drinking in humans, and chronic exposure in P animals can illuminate the molecular underpinnings of free-choice drinking in the liver. To address this gap, we captured the global, steady-state liver transcriptome following a 23 week free-choice, moderate alcohol consumption regimen (∼ 7.43 g ethanol/kg/day) in inbred alcohol-preferring (iP10a) rats. Chronic consumption led to down-regulation of nine genes in the cholesterol biosynthesis pathway, including HMG-CoA reductase, the rate-limiting step for cholesterol synthesis. These findings corroborate our phenotypic analyses, which indicate that this paradigm produced animals whose hepatic triglyceride levels, cholesterol levels and liver histology were indistinguishable from controls. These findings explain, at least in part, the J- or U-shaped relationship between cardiovascular risk and alcohol intake, and provide outstanding candidates for future studies aimed at understanding the mechanisms that underlie the salutary cardiovascular benefits of chronic low risk and nonhazardous alcohol intake.

We present a facile, simple method to detect DNA methylation by measuring the transverse proton relaxation behaviour. Positively charged nanoparticles are arranged along the negatively charged backbone of DNA strands through electrostatic interactions. The arrangement of NPs along DNA strands aids to amplify and compare the transverse proton relaxation signal for un-cut versus cut DNA strands cleaved by sequence specific restriction enzymes. Results from this study suggest that the presence of methylation on DNA can be detected using superparamagnetic NPs using NMR.