Rett syndrome (RTT), a neurodevelopmental disorder, is mainly caused by mutations in methyl CpG-binding protein 2 (MECP2), which has multiple functions such as binding to methylated DNA or interacting with a transcriptional co-repressor complex. It has been established that alterations in cyclin-dependent kinase-like 5 (CDKL5) or forkhead box protein G1 (FOXG1) correspond to distinct neurodevelopmental disorders, given that a series of studies have indicated that RTT is also caused by alterations in either one of these genes. We investigated the evolution and molecular features of MeCP2, CDKL5, and FOXG1 and their binding partners using phylogenetic profiling to gain a better understanding of their similarities. We also predicted the structural order-disorder propensity and assessed the evolutionary rates per site of MeCP2, CDKL5, and FOXG1 to investigate the relationships between disordered structure and other related properties with RTT. Here, we provide insight to the structural characteristics, evolution and interaction landscapes of those three proteins. We also uncovered the disordered structure properties and evolution of those proteins which may provide valuable information for the development of therapeutic strategies of RTT.
Abstract Pancreatic β cell clusters produce insulin and play a central role in glucose homeostasis. The regenerative capacity of mammalian β cells is limited and the loss of β cells causes diabetes. In contrast, zebrafish β cell clusters have a high regenerative capacity, making them an attractive model to study β cell cluster regeneration. How zebrafish β cell clusters regenerate, when the regeneration process is complete, and the identification of the cellular source of regeneration are fundamental questions that require investigation. Here, using larval and adult zebrafish, we demonstrate that pancreatic β cell clusters undergo a two-step regeneration process, regenerating functionality and then β cell numbers. Additionally, we found that all regenerating pancreatic β cells arose from Neurod1-expressing cells and that cells from different lineages contribute to both functional and β cell number recovery throughout their life. Furthermore, we found that during development and neogenesis, as well as regeneration, all β cells undergo Neurod1expression in zebrafish. Together, these results shed light on the fundamental cellular mechanisms underlying β cell cluster development, neogenesis, and regeneration.
Summary Sarcopenia is a geriatric syndrome characterized by an age-related decline in skeletal muscle mass and strength. Here, we show that suppression of mitochondrial calcium uniporter (MCU)-mediated Ca 2+ influx into mitochondria in the body wall muscles of the nematode Caenorhabditis elegans improved the sarcopenic phenotypes, blunting movement and mitochondrial structural and functional decline with age. We found that normally aged muscle cells exhibited elevated resting mitochondrial Ca 2+ levels and increased mitophagy to eliminate damaged mitochondria. Similar to aging muscle, we found that suppressing MCU function in muscular dystrophy improved movement via reducing elevated resting mitochondrial Ca 2+ levels. Taken together, our results reveal that elevated resting mitochondrial Ca 2+ levels contribute to muscle decline with age and in muscular dystrophy. Further, modulation of MCU activity may act as a potent pharmacological target in various conditions involving muscle loss.
Cell migration and axon guidance require proper regulation of the actin cytoskeleton in response to extracellular guidance cues. Rho/Rac small GTPases are essential regulators of actin remodeling. Caenorhabditis elegans CED-10 is a Rac1 homolog that is required for various cellular morphological changes and migration events and is under the control of several guidance signaling pathways. There is still considerable uncertainty regarding events following the activation of guidance receptors by extracellular signals and the regulation of actin dynamics based on spatiotemporally restricted Rac activity. Here we show that the VPS9 domain protein RIN-1 acts as a novel effector for CED-10 in C. elegans. The orthologous mammalian Rin1 protein has previously been identified as an effector for Ras GTPase and is now known to function as a guanine nucleotide exchange factor for Rab5 GTPase. We found that RIN-1 specifically binds to the GTP-bound form of CED-10 and that mutations in rin-1 cause significant defects in migration and axon guidance of restricted neuronal cell types including AVM and HSN neurons, in contrast to the various defects observed in ced-10 mutants. Our analyses place RIN-1 in the Slit-Robo genetic pathway that regulates repulsive signaling for dorsoventral axon guidance. In rin-1 mutants, actin accumulated on both the ventral and dorsal sides of the developing HSN neuron, in contrast to its ventral accumulation in wild type. These results strongly suggest that RIN-1 acts as an effector for CED-10/Rac1 and regulates actin remodeling in response to restricted guidance cues.
