Human epidemiological studies have shown that paternal aging as one of the risk factors for neurodevelopmental disorders, such as autism, in offspring. A recent study has suggested that factors other ...than de novo mutations due to aging can influence the biology of offspring. Here, we focused on epigenetic alterations in sperm that can influence developmental programs in offspring. In this study, we qualitatively and semiquantitatively evaluated histone modification patterns in male germline cells throughout spermatogenesis based on immunostaining of testes taken from young (3 months old) and aged (12 months old) mice. Although localization patterns were not obviously changed between young and aged testes, some histone modification showed differences in their intensity. Among histone modifications that repress gene expression, histone H3 lysine 9 trimethylation (H3K9me3) was decreased in the male germline cells of the aged testis, while H3K27me2/3 was increased. The intensity of H3K27 acetylation (ac), an active mark, was lower/higher depending on the stages in the aged testis. Interestingly, H3K27ac was detected on the putative sex chromosomes of round spermatids, while other chromosomes were occupied by a repressive mark, H3K27me3. Among other histone modifications that activate gene expression, H3K4me2 was drastically decreased in the male germline cells of the aged testis. In contrast, H3K79me3 was increased in M-phase spermatocytes, where it accumulates on the sex chromosomes. Therefore, aging induced alterations in the amount of histone modifications and in the differences of patterns for each modification. Moreover, histone modifications on the sex chromosomes and on other chromosomes seems to be differentially regulated by aging. These findings will help elucidate the epigenetic mechanisms underlying the influence of paternal aging on offspring development.
The TRPV4 calcium-permeable cation channel plays important physiological roles in osmosensation, mechanosensation, cell barrier formation, and bone homeostasis. Recent studies reported that mutations ...in TRPV4, including some in its ankyrin repeat domain (ARD), are associated with human inherited diseases, including neuropathies and skeletal dysplasias, probably because of the increased constitutive activity of the channel. TRPV4 activity is regulated by the binding of calmodulin and small molecules such as ATP to the ARD at its cytoplasmic N-terminus. We determined structures of ATP-free and -bound forms of human TRPV4-ARD and compared them with available TRPV-ARD structures. The third inter-repeat loop region (Finger 3 loop) is flexible and may act as a switch to regulate channel activity. Comparisons of TRPV-ARD structures also suggest an evolutionary link between ARD structure and ATP binding ability. Thermal stability analyses and molecular dynamics simulations suggest that ATP increases stability in TRPV-ARDs that can bind ATP. Biochemical analyses of a large panel of TRPV4-ARD mutations associated with human inherited diseases showed that some impaired thermal stability while others weakened ATP binding ability, suggesting molecular mechanisms for the diseases.
The subcommissural organ (SCO) is a circumventricular organ highly conserved in vertebrates from
such as lamprey to mammals including human. The SCO locates in the boundary between the third ...ventricle and the entrance of the aqueduct of Sylvius. The SCO functions as a secretory organ producing a variety of proteins such as SCO-spondin, transthyretin, and basic fibroblast growth factor (FGF) into the cerebrospinal fluid (CSF). A significant contribution of the SCO has been thought to maintain the homeostasis of CSF dynamics. However, evidence has shown a possible role of SCO on neurogenesis in the adult brain. This review highlights specific features of the SCO related to adult neurogenesis, suggested by the progress of understanding SCO functions. We begin with a brief history of the SCO discovery and continue to structural features, gene expression, and a possible role in adult neurogenesis suggested by the SCO transplant experiment.
Depression is a global burden with profound personal and economic consequences. Previous studies have reported that the amount of physical activity is associated with depression. However, the ...relationship between the temporal patterns of physical activity and depressive symptoms is poorly understood. In this exploratory study, we hypothesize that a particular temporal pattern of daily physical activity could be associated with depressive symptoms and might be a better marker than the total amount of physical activity.
To address the hypothesis, we investigated the association between depressive symptoms and daily dominant activity behaviors based on 24-h temporal patterns of physical activity. We conducted a cross-sectional study on NHANES 2011-2012 data collected from the noninstitutionalized civilian resident population of the United States. The number of participants that had the whole set of physical activity data collected by the accelerometer is 6613. Among 6613 participants, 4242 participants had complete demography and Patient Health Questionnaire-9 (PHQ-9) questionnaire, a tool to quantify depressive symptoms. The association between activity-count behaviors and depressive symptoms was analyzed using multivariable logistic regression to adjust for confounding factors in sequential models.
We identified four physical activity-count behaviors based on five physical activity-counting patterns classified by unsupervised machine learning. Regarding PHQ-9 scores, we found that evening dominant behavior was positively associated with depressive symptoms compared to morning dominant behavior as the control group.
Our results might contribute to monitoring and identifying individuals with latent depressive symptoms, emphasizing the importance of nuanced activity patterns and their probability of assessing depressive symptoms effectively.
•Fatty acids act as building blocks, energy sources, and signaling molecules in cells.•Fatty acid binding proteins regulate various physiological responses.•Polyunsaturated fatty acids are an ...important factor in the brain function.•FABPs may be involved with psychiatric disorders through neurogenesis in the brain.•Suitable PUFA supply could be a therapeutic/preventive approach for mental illness.
The brain is rich in lipid and fatty molecules. In this review article, we focus on fatty acid binding proteins (Fabps) that bind to fatty acids such as arachidonic acid and docosahexianoic acid and transfer these lipid ligands within the cytoplasm. Among Fabp family molecules, Fabp3, Fabp5, and Fabp7 are specifically localized in neural stem/progenitor cells, neurons and glia in a cell-type specific manner. Quantitative trait locus analysis has revealed that Fabp7 is related with performance of prepulse inhibition (PPI) that is used as an endophenotype of psychiatric diseases such as schizophrenia. Fabp5 and Fabp7 play important roles on neurogenesis and differentially regulate acoustic startle response and PPI. However, other behavior performances including spatial memory, anxiety-like behavior, and diurnal changes in general activity were not different in mice deficient for Fabp7 or Fabp5. Considering the importance of fatty acids in neurogenesis, we would like to emphasize that lipid nutrition and its dynamism via Fabps play significant roles in mental conditions. This might provide a good example of how nutritional environment can affect psychiatric conditions at the molecular level.
Corticogenesis is one of the most critical and complicated processes during embryonic brain development. Any slight impairment in corticogenesis could cause neurodevelopmental disorders such as ...Fragile X syndrome (FXS), of which symptoms contain intellectual disability (ID) and autism spectrum disorder (ASD). Fragile X mental retardation protein (FMRP), an RNA-binding protein responsible for FXS, shows strong expression in neural stem/precursor cells (NPCs) during corticogenesis, although its function during brain development remains largely unknown. In this study, we attempted to identify the FMRP target mRNAs in the cortical primordium using RNA immunoprecipitation sequencing analysis in the mouse embryonic brain. We identified 865 candidate genes as targets of FMRP involving 126 and 118 genes overlapped with ID and ASD-associated genes, respectively. These overlapped genes were enriched with those related to chromatin/chromosome organization and histone modifications, suggesting the involvement of FMRP in epigenetic regulation. We further identified a common set of 17 FMRP "core" target genes involved in neurogenesis/FXS/ID/ASD, containing factors associated with Ras/mitogen-activated protein kinase, Wnt/β-catenin, and mammalian target of rapamycin (mTOR) pathways. We indeed showed overactivation of mTOR signaling via an increase in mTOR phosphorylation in the Fmr1 knockout (Fmr1 KO) neocortex. Our results provide further insight into the critical roles of FMRP in the developing brain, where dysfunction of FMRP may influence the regulation of its mRNA targets affecting signaling pathways and epigenetic modifications.
Animals use their gustatory systems to evaluate the nutritious value, toxicity, sodium content, and acidity of food. Although characterization of molecular identities that receive taste chemicals is ...essential, molecular receptors underlying sour taste sensation remain unclear. Here, we show that two transient receptor potential (TRP) channel members, PKD1L3 and PKD2L1, are coexpressed in a subset of taste receptor cells in specific taste areas. Cells expressing these molecules are distinct from taste cells having receptors for bitter, sweet, or umami tastants. The PKD2L1 proteins are accumulated at the taste pore region, where taste chemicals are detected. PKD1L3 and PKD2L1 proteins can interact with each other, and coexpression of the PKD1L3 and PKD2L1 is necessary for their functional cell surface expression. Finally, PKD1L3 and PKD2L1 are activated by various acids when coexpressed in heterologous cells but not by other classes of tastants. These results suggest that PKD1L3 and PKD2L1 heteromers may function as sour taste receptors.
Advanced paternal age can have deleterious effects on various traits in the next generation. Here, we establish a paternal‐aging model in mice to understand the molecular mechanisms of ...transgenerational epigenetics. Whole‐genome target DNA methylome analyses of sperm from aged mice reveal more hypo‐methylated genomic regions enriched in REST/NRSF binding motifs. Gene set enrichment analyses also reveal the upregulation of REST/NRSF target genes in the forebrain of embryos from aged fathers. Offspring derived from young mice administrated with a DNA de‐methylation drug phenocopy the abnormal vocal communication of pups derived from aged fathers. In conclusion, hypo‐methylation of sperm DNA can be a key molecular feature modulating neurodevelopmental programs in offspring by causing fluctuations in the expression of REST/NRSF target genes.
SYNOPSIS
Paternal aging affects health and disease of the next generation, but the causative mechanisms are largely unknown. This study identifies hypo‐methylated sites enriched in REST/NRSF motifs in sperm DNA as epigenetic key features for inheritance.
Paternal aging induces vocal communication deficits in pups at the infant stage.
Sperm DNA from aged mice contains 96 hypo‐methylated regions enriched in REST/NRSF motives.
REST signature genes are upregulated in the embryonic brain of the offspring of aged fathers.
Offspring of young mice treated with a DNA de‐methylating drug phenocopy vocal communication deficits.
Paternal aging affects health and disease of the next generation, but the causative mechanisms are largely unknown. This study identifies hypo‐methylated sites enriched in REST/NRSF motifs in sperm DNA as epigenetic key features for inheritance.
Lactate serves as the major glucose alternative to an energy substrate in the brain. Lactate level is increased in the fetal brain from the middle stage of gestation, indicating the involvement of ...lactate in brain development and neuronal differentiation. Recent reports show that lactate functions as a signaling molecule to regulate gene expression and protein stability. However, the roles of lactate signaling in neuronal cells remain unknown. Here, we showed that lactate promotes the all stages of neuronal differentiation of SH-SY5Y and Neuro2A, human and mouse neuroblastoma cell lines, characterized by increased neuronal marker expression and the rates of neurites extension. Transcriptomics revealed many lactate-responsive genes sets such as SPARCL1 in SH-SY5Y, Neuro2A, and primary embryonic mouse neuronal cells. The effects of lactate on neuronal function were mainly mediated through monocarboxylate transporters 1 (MCT1). We found that NDRG family member 3 (NDRG3), a lactate-binding protein, was highly expressed and stabilized by lactate treatment during neuronal differentiation. Combinative RNA-seq of SH-SY5Y with lactate treatment and NDRG3 knockdown shows that the promotive effects of lactate on neural differentiation are regulated through NDRG3-dependent and independent manners. Moreover, we identified TEA domain family member 1 (TEAD1) and ETS-related transcription factor 4 (ELF4) are the specific transcription factors that are regulated by both lactate and NDRG3 in neuronal differentiation. TEAD1 and ELF4 differently affect the expression of neuronal marker genes in SH-SY5Y cells. These results highlight the biological roles of extracellular and intracellular lactate as a critical signaling molecule that modifies neuronal differentiation.
Synaptic pruning is a fundamental process of neuronal circuit refinement in learning and memory. Accumulating evidence suggests that glia participates in sculpting the neuronal circuits through ...synapse engulfment. However, whether glial involvement in synaptic pruning has a role in memory formation remains elusive. Using newly developed phagocytosis reporter mice and three-dimensional ultrastructural characterization, we found that synaptic engulfment by cerebellar Bergmann glia (BG) frequently occurred upon cerebellum-dependent motor learning in mice. We observed increases in pre- and postsynaptic nibbling by BG along with a reduction in spine volume after learning. Pharmacological blockade of engulfment with Annexin V inhibited both the spine volume reduction and overnight improvement of motor adaptation. These results indicate that BG contribute to the refinement of the mature cerebellar cortical circuit through synaptic engulfment during motor learning.
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