Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Heritability and polygenic predictionIn the EUR sample, the SNP-based heritability (h 2 SNP ) (that is, the proportion of variance in liability attributable to all measured SNPs)

Graphical Abstract Highlights d SynGO is a public knowledge base and online analysis platform for synapse research d SynGO has annotated 1,112 genes with synaptic localization and/or function d SynGO genes are exceptionally large, well conserved, and intolerant to mutations d SynGO genes are strongly enriched among genes associated with brain disorders Correspondence guus.smit@cncr.vu.nl (A.B.S.), matthijs@cncr.vu.nl (M.V.) In BriefThe SynGO consortium presents a framework to annotate synaptic protein locations and functions and annotations for 1,112 synaptic genes based on published experimental evidence. SynGO reports exceptional features and disease associations for synaptic genes and provides an online data analysis platform. SUMMARYSynapses are fundamental information-processing units of the brain, and synaptic dysregulation is central to many brain disorders (''synaptopathies''). However, systematic annotation of synaptic genes and ontology of synaptic processes are currently lacking. We established SynGO, an interactive knowledge base that accumulates available research about synapse biology using Gene Ontology (GO) annotations to novel ontology terms: 87 synaptic locations and 179 synaptic processes. SynGO annotations are exclusively based on published, expert-curated evidence. Using 2,922 annotations for 1,112 genes, we show that synaptic genes are exceptionally well conserved and less tolerant to mutations than other genes. Many SynGO terms are significantly overrepresented among gene variations associated with intelligence, educational attainment, ADHD, autism, and bipolar disorder and among de novo variants associated with neurodevelopmental disorders, including schizophrenia. SynGO is a public, universal reference for synapse research and an online analysis platform for interpretation of large-scale -omics data (https://syngoportal.org and

Autism spectrum disorders (ASDs) are four times more common in males than in females, but the underlying mechanisms are poorly understood. We characterized sexually dimorphic changes in mice carrying a heterozygous mutation in Chd8 (Chd8) that was first identified in human CHD8 (Asn2373LysfsX2), a strong ASD-risk gene that encodes a chromatin remodeler. Notably, although male mutant mice displayed a range of abnormal behaviors during pup, juvenile, and adult stages, including enhanced mother-seeking ultrasonic vocalization, enhanced attachment to reunited mothers, and isolation-induced self-grooming, their female counterparts do not. This behavioral divergence was associated with sexually dimorphic changes in neuronal activity, synaptic transmission, and transcriptomic profiles. Specifically, female mice displayed suppressed baseline neuronal excitation, enhanced inhibitory synaptic transmission and neuronal firing, and increased expression of genes associated with extracellular vesicles and the extracellular matrix. Our results suggest that a human CHD8 mutation leads to sexually dimorphic changes ranging from transcription to behavior in mice.

Dishevelled (Dvl) is a key regulator of Wnt signaling both in the canonical and non-canonical pathways. Here we report the identification of a regulatory domain of ubiquitination (RDU) in the C-terminus of Dvl. Mutations in the RDU resulted in accumulation of polyubiquitinated forms of Dvl, which were mainly K63 linked. Small interfering RNA-based screening identified Usp14 as a mediator of Dvl deubiquitination. Genetic and chemical suppression of Usp14 activity caused an increase in Dvl polyubiquitination and significantly impaired downstream Wnt signaling. These data suggest that Usp14 functions as a positive regulator of the Wnt signaling pathway. Consistently, tissue microarray analysis of colon cancer revealed a strong correlation between the levels of Usp14 and β-catenin, which suggests an oncogenic role for Usp14 via enhancement of Wnt/β-catenin signaling.

Mest (mesoderm-specific transcript)/Peg1 (paternally expressed gene 1) is an imprinted gene that plays important roles in embryo development, although its biochemical role has not been determined. Ectopic expression of Mest/Peg1 inhibited Wnt-mediated reporter activity by enhancing the ubiquitination of β-catenin. The maturation and plasma membrane localization of the Wnt co-receptor LRP6 [LDLR (low-density lipoprotein receptor)-related protein 6], which are both necessary for Wnt signalling, were blocked by the expression of Mest/Peg1. Mest/Peg1 inhibited maturation of LRP6 by controlling the glycosylation of LRP6. Knockdown of Mest/Peg1, which might enhance Wnt signalling, blocked adipogenic differentiation of 3T3-L1 cells. Overall, our results suggest that Mest/Peg1 is a novel regulator of Wnt/β-catenin signalling during adipogenic differentiation.

Background: Autism spectrum disorders (ASD) involve neurodevelopmental dysregulations that lead to visible symptoms at early stages of life. Many ASD-related mechanisms suggested by animal studies are supported by demonstrated improvement in autistic-like phenotypes in adult animals following experimental reversal of dysregulated mechanisms. However, whether such mechanisms also act at earlier stages to cause autistic-like phenotypes is unclear. Methods: We used Shank2 −/− mice carrying a mutation identified in human ASD (exons 6 and 7 deletion) and combined electrophysiological and behavioral analyses to see if early pathophysiology at pup stages is different from late pathophysiology at juvenile and adult stages, and correcting early pathophysiology can normalize late pathophysiology and abnormal behaviors in juvenile and adult mice. Results: Early correction of a dysregulated mechanism in young mice prevents manifestation of autistic-like social behaviors in adult mice. Shank2 −/− mice, known to display N-methyl-Daspartate receptor (NMDAR) hypofunction and autistic-like behaviors at post-weaning stages after postnatal day 21 (P21), show the opposite synaptic phenotype-NMDAR hyperfunction-at an earlier pre-weaning stage (~P14). Moreover, this NMDAR hyperfunction at P14 rapidly shifts to NMDAR hypofunction after weaning (~P24). Chronic suppression of the early NMDAR hyperfunction by the NMDAR antagonist memantine (P7-21) prevents NMDAR hypofunction and autistic-like social behaviors from manifesting at later stages (~P28 and P56).

Glycine transporters (GlyT1 and GlyT2) that regulate levels of brain glycine, an inhibitory neurotransmitter with co‐agonist activity for NMDA receptors (NMDARs), have been considered to be important targets for the treatment of brain disorders with suppressed NMDAR function such as schizophrenia. However, it remains unclear whether other amino acid transporters expressed in the brain can also regulate brain glycine levels and NMDAR function. Here, we report that SLC6A20A, an amino acid transporter known to transport proline based on in vitro data but is understudied in the brain, regulates proline and glycine levels and NMDAR function in the mouse brain. SLC6A20A transcript and protein levels were abnormally increased in mice carrying a mutant PTEN protein lacking the C terminus through enhanced β‐catenin binding to the Slc6a20a gene. These mice displayed reduced extracellular levels of brain proline and glycine and decreased NMDAR currents. Elevating glycine levels back to normal ranges by antisense oligonucleotide‐induced SLC6A20 knockdown, or the competitive GlyT1 antagonist sarcosine, normalized NMDAR currents and repetitive climbing behavior observed in these mice. Conversely, mice lacking SLC6A20A displayed increased extracellular glycine levels and NMDAR currents. Lastly, both mouse and human SLC6A20 proteins mediated proline and glycine transports, and SLC6A20 proteins could be detected in human neurons. These results suggest that SLC6A20 regulates proline and glycine homeostasis in the brain and that SLC6A20 inhibition has therapeutic potential for brain disorders involving NMDAR hypofunction.

Wnt signaling is implicated in a variety of developmental and pathological processes. The molecular mechanisms governing the secretion of Wnt ligands remain to be elucidated. Wntless, an evolutionarily conserved multipass transmembrane protein, is a dedicated secretion factor of Wnt proteins that participates in Drosophila melanogaster embryogenesis. In this study, we show that Xenopus laevis Wntless (XWntless) regulates the secretion of a specific Wnt ligand, XWnt4, and that this regulation is specifically required for eye development in Xenopus. Moreover, the Retromer complex is required for XWntless recycling to regulate the XWnt4-mediated eye development. Inhibition of Retromer function by Vps35 morpholino (MO) resulted in various Wnt deficiency phenotypes, affecting mesoderm induction, gastrulation cell movements, neural induction, neural tube closure, and eye development. Overexpression of XWntless led to the rescue of Vps35 MO-mediated eye defects but not other deficiencies. These results collectively suggest that XWntless and the Retromer complex are required for the efficient secretion of XWnt4, facilitating its role in Xenopus eye development.The Wnt family of glycoproteins comprises one of the largest families of paracrine factors essential for embryonic development and adult tissue homeostasis (reviewed at the Wnt Homepage, http://www.stanford.edu/ϳrnusse/wntwindow .html). It regulates several aspects of biological processes, including cell fate specification, proliferation, migration, and polarity formation (29, 48). The Wnt signaling pathway is initiated by Wnt ligands secreted from Wnt-producing cells. The ligands bind to frizzled receptors and coreceptors expressed on the receiving cells. Wnt ligand perception (5,24,46,49), signaling cascades into receiving cells (8,27), and the consequences of gene expression (17) or cytoskeletal changes (36) are well documented in various contexts. However, relatively limited information is available about the processes in Wnt-producing cells and extracellular spaces. The establishment of the concentration gradient of the Wnt ligand in the extracellular space is mediated by lipoprotein particle formation (33). The Retromer complex is additionally required in Wnt-producing cells and for long-range secretion of Wnt (12). Porcupine is essential for posttranslational modifications, which may be essential for the proper folding and secretion of Wnt ligands (28).Recent achievements in Drosophila melanogaster genetics and genomic RNA interference screening have revealed the existence of a new component of the Wnt secretory pathway, specifically, a dedicated secretion factor of Wg designated Wntless (2), Evi (3), or Sprinter (16). Wntless is an evolutionarily conserved multipass transmembrane protein required solely for Wg secretion. Wntless is not essential for the palmitoylation of Wg, indicating that it does not act on functional Wg production, like Porcupine, another evolutionarily conserved multipass transmembrane protein. Wntless is a regulator of intracellular W...