Extended dendralenes through cumulene polymerization
Related Articles
The WAVE complex in developmental and adulthood brain disorders
Actin polymerization and depolymerization are fundamental cellular processes required not only for the embryonic and postnatal development of the brain but also for the maintenance of neuronal plasticity and survival in the adult and aging brain. The orchestrated organization of actin filaments is controlled by various actin regulatory proteins. Wiskott‒Aldrich syndrome protein-family verprolin-homologous protein (WAVE) members are key activators of ARP2/3 complex-mediated actin polymerization. WAVE proteins exist as heteropentameric complexes together with regulatory proteins, including CYFIP, NCKAP, ABI and BRK1. The activity of the WAVE complex is tightly regulated by extracellular cues and intracellular signaling to execute its roles in specific intracellular events in brain cells. Notably, dysregulation of the WAVE complex and WAVE complex-mediated cellular processes confers vulnerability to a variety of brain disorders. De novo mutations in WAVE genes and other components of the WAVE complex have been identified in patients with developmental disorders such as intellectual disability, epileptic seizures, schizophrenia, and/or autism spectrum disorder. In addition, alterations in the WAVE complex are implicated in the pathophysiology of Alzheimer’s disease and Parkinson’s disease, as well as in behavioral adaptations to psychostimulants or maladaptive feeding.
A network of interacting ciliary tip proteins with opposing activities imparts slow and processive microtubule growth
Cilia are motile or sensory organelles present on many eukaryotic cells. Their formation and function rely on axonemal microtubules, which exhibit very slow dynamics, but the underlying mechanisms are largely unexplored. Here we reconstituted in vitro the individual and collective activities of the ciliary tip module proteins CEP104, CSPP1, TOGARAM1, ARMC9 and CCDC66, which interact with each other and with microtubules and, when mutated in humans, cause ciliopathies such as Joubert syndrome. We show that CEP104, a protein with a tubulin-binding TOG domain, and its luminal partner CSPP1 inhibit microtubule growth and shortening. Another TOG-domain protein, TOGARAM1, overcomes growth inhibition imposed by CEP104 and CSPP1. CCDC66 and ARMC9 do not affect microtubule dynamics but act as scaffolds for their partners. Cryo-electron tomography demonstrated that, together, ciliary tip module members form plus-end-specific cork-like structures that reduce protofilament flaring. The combined effect of these proteins is very slow processive microtubule elongation, which recapitulates axonemal dynamics in cells.
Sensory input, sex and function shape hypothalamic cell type development
Mammalian behaviour and physiology undergo major changes in early life. Young animals rely on conspecifics to meet their needs and start showing nutritional independence and sex-specific social interactions at weaning and puberty, respectively. How neuronal populations regulating homeostatic functions and social behaviours develop during these transitions remains unclear. We used paired transcriptomic and chromatin accessibility profiling to examine the developmental trajectories of neuronal populations in the hypothalamic preoptic region, where cell types with key roles in physiological and behavioural control have been identified1,2,3,4,5,6. These data show a marked diversity of developmental trajectories shaped by the sex of the animal, and the location and behavioural or physiological function of the corresponding cell types. We identify key stages of preoptic development, including early diversification, perinatal emergence of sex differences, postnatal maturation and refinement of signalling networks, and nonlinear transcriptional changes accelerating at the time of weaning and puberty. We assessed preoptic development in various sensory mutants and find a major role for vomeronasal sensing in the timing of preoptic cell type maturation. These results provide new insights into the development of neurons controlling homeostatic functions and social behaviours and lay ground for examining the dynamics of these functions in early life.
Kdm2a inhibition in skeletal muscle improves metabolic flexibility in obesity
Skeletal muscle is a critical organ in maintaining homoeostasis against metabolic stress, and histone post-translational modifications are pivotal in those processes. However, the intricate nature of histone methylation in skeletal muscle and its impact on metabolic homoeostasis have yet to be elucidated. Here, we report that mitochondria-rich slow-twitch myofibers are characterized by significantly higher levels of H3K36me2 along with repressed expression of Kdm2a, an enzyme that specifically catalyses H3K36me2 demethylation. Deletion or inhibition of Kdm2a shifts fuel use from glucose under cold challenge to lipids under obese conditions by increasing the proportion of mitochondria-rich slow-twitch myofibers. This protects mice against cold insults and high-fat-diet-induced obesity and insulin resistance. Mechanistically, Kdm2a deficiency leads to a marked increase in H3K36me2 levels, which then promotes the recruitment of Mrg15 to the Esrrg locus to process its precursor messenger RNA splicing, thereby reshaping skeletal muscle metabolic profiles to induce slow-twitch myofiber transition. Collectively, our data support the role of Kdm2a as a viable target against metabolic stress.
Selection for somatic escape variants in SERPINA1 in the liver of patients with alpha-1 antitrypsin deficiency
Somatic variants accumulate in non-malignant tissues with age. Functional variants, leading to clonal advantage of hepatocytes, accumulate in the liver of patients with acquired chronic liver disease (CLD). Whether somatic variants are common to CLD from differing etiologies is unknown. We analyzed liver somatic variants in patients with genetic CLD from alpha-1 antitrypsin (A1AT) deficiency or hemochromatosis. We show that somatic variants in SERPINA1, the gene encoding A1AT, are strongly selected for in A1AT deficiency, with evidence of convergent evolution. Acquired SERPINA1 variants are clustered at the carboxyl terminus of A1AT, leading to truncation. In vitro and in vivo, C-terminal truncation variants reduce disease-associated Z-A1AT polymer accumulation and disruption of the endoplasmic reticulum, supporting the C-terminal domain swap mechanism. Therefore, somatic escape variants from a deleterious germline variant are selected for in A1AT deficiency, suggesting that functional somatic variants are disease-specific in CLD and point to disease-associated mechanisms.
Responses