Large Number Of Genes Research Articles

Transcriptome Comparison between Two Strains of Ustilago esculenta during the Mating.

Ustilago esculenta is a smut fungus that obligately infects Zizania latifolia and stimulates tissue swelling to form galls. Unlike T-type, MT-type U. esculenta can only proliferate within plant tissues and infect the offspring of their host. Production of telispores, haploid life, and plant cuticle penetration are not essential for it, which may lead to the degeneration in these processes. Transcriptome changes during the mating of T- and MT-type U. esculenta were studied. The functions of several secreted proteins were further confirmed by knock-out mutants. Our results showed that MT-type U. esculenta can receive environmental signals in mating and circumstance sensing as T-type does. However, MT-type U. esculenta takes a longer time for conjunction tube formation and cytoplasmic fusion. A large number of genes encoding secreted proteins are enriched in the purple co-expression module. They are significantly up-regulated in the late stage of mating in T-type U. esculenta, indicating their relationship with infecting. The knock-out of g6161 (xylanase) resulted in an attenuated symptom. The knock-out of g943 or g4344 (function unidentified) completely blocked the infection at an early stage. This study provides a comprehensive comparison between T- and MT-type during mating and identifies two candidate effectors for further study.

Development of a comprehensive approach to adult hereditary cancer testing in Ontario

BackgroundGenetic testing for hereditary cancer susceptibility has advanced over time due to the discovery of new risk genes, improved technology and decreased cost. In the province of Ontario, testing eligibility...

High-resolution sequencing of nine elite upland cotton cultivars uncovers genic variations and breeding improvement targets.

Structural variations (SVs) are critical factors affecting genome evolution and important traits. However, identification results and functional analyses of SVs in upland cotton are rare. Here, based on the genetic relationships, breeding history and cumulative planting area of upland cotton in China, nine predominant cultivars from the past 60 years (1950s-2010s) were selected for long read sequencing to uncover genic variations and breeding improvement targets for this crop. Based on the ZM24 reference genome, 0.88-1.47 × 104 SVs per cultivar were identified, and an SV set was constructed. SVs affected the expression of a large number of genes during fiber elongation, and a transposable element insertion resulted in the glandless phenotype in upland cotton. Six widespread inversions were identified based on nine draft genomes and high-throughput chromosome conformation capture data. Multiple haplotype blocks that were always associated with aggregated SVs were demonstrated to play a pivotal role in the agronomic traits of upland cotton and drove its adaptation to the northern planting region. Exotic introgression was the source of these haplotype blocks and increased the genetic diversity of upland cotton. Our results enrich the genome resources of upland cotton, and the identified SVs will promote genetic and breeding research in cotton.

Further fine mapping and candidate gene prediction for a new restoring fertility gene Rf(fa) in rice

Rf(fa), a new restoring fertility gene in rice, was previously located to a large region on Chromosome 10. The large number of genes within the region made cloning of Rf(fa) difficult. To perform the cloning and further elucidate the molecular mechanism, we reconstructed a mapping segregation population (BC<sub>1</sub>F<sub>1</sub>) of 12 000 plants. Using the population and polymorphism of simple sequence repeat (SSR) molecular markers, we finally mapped Rf(fa) between the two SSR molecular markers MM2000 and RM25658, within a 78.87 kb region. By de novo sequencing of a restoring line of CMS-FA hybrid rice, we obtained the genomic sequence of the mapping region, which provided the basis for the prediction of the candidate gene(s) of the target gene and for the comparison of genomic sequence differences between wild and cultivated rice. Within the mapping region, the genomic sequence of the wild rice was significantly different from that of cultivated rice. There were ten genes in the final mapping region. A pentatricopeptide repeat (PPR) protein gene was predicted as the candidate gene of Rf(fa). Our results laid a solid foundation for the final cloning and molecular mechanism analysis of the gene. The identified molecular markers tightly linked to Rf(fa) will facilitate the marker assisted selection in breeding of CMS-FA hybrid rice.

Inference of regulatory networks through temporally sparse data.

A major goal in genomics is to properly capture the complex dynamical behaviors of gene regulatory networks (GRNs). This includes inferring the complex interactions between genes, which can be used for a wide range of genomics analyses, including diagnosis or prognosis of diseases and finding effective treatments for chronic diseases such as cancer. Boolean networks have emerged as a successful class of models for capturing the behavior of GRNs. In most practical settings, inference of GRNs should be achieved through limited and temporally sparse genomics data. A large number of genes in GRNs leads to a large possible topology candidate space, which often cannot be exhaustively searched due to the limitation in computational resources. This paper develops a scalable and efficient topology inference for GRNs using Bayesian optimization and kernel-based methods. Rather than an exhaustive search over possible topologies, the proposed method constructs a Gaussian Process (GP) with a topology-inspired kernel function to account for correlation in the likelihood function. Then, using the posterior distribution of the GP model, the Bayesian optimization efficiently searches for the topology with the highest likelihood value by optimally balancing between exploration and exploitation. The performance of the proposed method is demonstrated through comprehensive numerical experiments using a well-known mammalian cell-cycle network.

Understanding the physiological and molecular mechanism of salinity stress tolerance in plants

Salinity is considered a global threat to agriculture and causes a significant reduction in crop yield. In particular, salinity stress promotes reactive oxygen species (ROS) accumulation and ionic imbalance in cells, leading to oxidative stress and even cell death. A large number of genes which are involved in defense, hormone, carbohydrate and metabolic pathways are down-regulated under salinity stress. Plants respond to salinity stress through a series of physiological and molecular mechanisms including antioxidant enzymes, hormones, defense related genes and signaling pathway activation. Plant defense systems modulate the overproduction of ROS through the activation of stress responsive-genes such as superoxide dismutase (SOD), peroxidase (POD), catalase (CAT) and glutamine synthetase (GS) and transcription factors such as MYBs, WRKY, and ERF. The salt overly sensitive (SOS) pathway is potentially involved in salt stress tolerance. SOS1, SOS3 and SOS2 are required for the oxidative stress tolerance by reducing the uptakes, and inter-cellular and intra-cellular distribution of Na+ and Cl−. This review discusses the discovery of stress-responsive genes and signaling pathways, and summarizes the research progress on the regulatory mechanisms of salinity stress tolerance in plants, which will help accelerate breeding programs for salinity stress tolerance.

A framework for improving wheat spike development and yield based on the master regulatory TOR and SnRK gene systems.

The low rates of yield gain in wheat breeding programs create an ominous situation for the world. Amongst the reasons for this low rate are issues manifested in spike development that result in too few spikelets, fertile florets, and therefore grains being produced. Phases in spike development are particularly sensitive to stresses of various kinds and origins, and these are partly responsible for the deficiencies in grain production and slow rates of gain in yield. The diversity of developmental processes, stresses, and the large numbers of genes involved make it particularly difficult to prioritize approaches in breeding programs without an overarching, mechanistic framework. Such a framework, introduced here, is provided around the master regulator target of rapamycin and sucrose non-fermenting-1 (SNF1)-related protein kinase complexes and their control by trehalose-6-phosphate and other molecules. Being master regulators of the balance between growth and growth inhibition under stress, these provide genetic targets for creating breakthroughs in yield enhancement. Examples of potential targets and experimental approaches are described.

Comparative Transcriptome Analysis Unravels the Response Mechanisms of Fusarium oxysporum f.sp. cubense to a Biocontrol Agent, Pseudomonas aeruginosa Gxun-2

Banana Fusarium wilt, which is caused by Fusarium oxysporum f.sp. cubense Tropical Race 4 (FOC TR4), is one of the most serious fungal diseases in the banana-producing regions in east Asia. Pseudomonas aeruginosa Gxun-2 could significantly inhibit the growth of FOC TR4. Strain Gxun-2 strongly inhibited the mycelial growth of FOC TR4 on dual culture plates and caused hyphal wrinkles, ruptures, and deformities on in vitro cultures. Banana seedlings under pot experiment treatment with Gxun-2 in a greenhouse resulted in an 84.21% reduction in the disease. Comparative transcriptome analysis was applied to reveal the response and resistance of FOC TR4 to Gxun-2 stress. The RNA-seq analysis of FOC TR4 during dual-culture with P. aeruginosa Gxun-2 revealed 3075 differentially expressed genes (DEGs) compared with the control. Among the genes, 1158 genes were up-regulated, and 1917 genes were down-regulated. Further analysis of gene function and the pathway of DEGs revealed that genes related to the cell membrane, cell wall formation, peroxidase, ABC transporter, and autophagy were up-regulated, while down-regulated DEGs were enriched in the sphingolipid metabolism and chitinase. These results indicated that FOC TR4 upregulates a large number of genes in order to maintain cell functions. The results of qRT-PCR conducted on a subset of 13 genes were consistent with the results of RNA-seq data. Thus, this study serves as a valuable resource regarding the mechanisms of fungal pathogen resistance to biocontrol agents.

Characterizing corn-straw-degrading actinomycetes and evaluating application efficiency in straw-returning experiments.

Corn straw is an abundant lignocellulose resource and by-product of agricultural production. With the continuous increase in agricultural development, the output of corn straw is also increasing significantly. However, the inappropriate disposal of straw results in wasting of resources, and also causes a serious ecological crisis. Screening microorganisms with the capacity to degrade straw and understanding their mechanism of action is an efficient approach to solve such problems. For this purpose, our research group isolated three actinomycete strains with efficient lignocellulose degradation ability from soil in the cold region of China: Streptomyces sp. G1T, Streptomyces sp. G2T and Streptomyces sp. G3T. Their microbial properties and taxonomic status were assessed to improve our understanding of these strains. The three strains showed typical characteristics of the genus Streptomyces, and likely represent three different species. Genome functional annotation indicated that most of their genes were related to functions like carbohydrate transport and metabolism. In addition, a similar phenomenon also appeared in the COG and CAZyme analyses, with a large number of genes encoding carbohydrate-related hydrolases, such as cellulase, glycosidase and endoglucanase, which could effectively destroy the structure of lignocellulose in corn straw. This unambiguously demonstrated the potential of the three microorganisms to hydrolyze macromolecular polysaccharides at the molecular level. In addition, in the straw-returning test, the decomposing consortium composed of the three Streptomyces isolates (G123) effectively destroyed the recalcitrant bonds between the various components of straw, and significantly reduced the content of active components in corn straw. Furthermore, microbial diversity analysis indicated that the relative abundance of Proteobacteria, reportedly associated with soil antibiotic resistance and antibiotic degradation, was significantly improved with straw returning at both tested time points. The microbial diversity of each treatment was also dramatically changed by supplementing with G123. Taken together, G123 has important biological potential and should be further studied, which will provide new insights and strategies for appropriate treatment of corn straw.

Differential Gene Expression Analysis and Gene Ontology in Triploid and Diploid Pocillopora Acuta

Corals are marine invertebrates that are facing life-threatening environmental stressors due to climate change. Polyploidy can, in such cases, be an important source of variation and adaptation in corals and other species. Polyploidy is the genomic condition wherein the cells of a normally diploid organism have more than one pair of chromosomes. Pocillopora acuta, also known as the cauliflower coral, is a brooding coral that can also reproduce asexually. It is a stress-sensitive coral, which means it shows clear physiological changes in response to environmental stressors like temperature, salinity, and pH. In this study, about 60% of the stony coral Pocillopora acuta samples collected from Kāneʻohe Bay, Oahu, HI, were triploid. The aim of this study was to identify the differences in gene expression patterns between triploid cluster 1 (T1), triploid cluster 2 (T2), and diploid samples (D) of P. acuta. Pairwise comparisons were carried out between all categories: T1 vs. D, T2 vs. D, and T1 vs. T2. While there were a large number of genes exhibiting similar expression patterns in both triploid clusters, many genes were differentially regulated in T1 when compared to T2. This result provides evidence suggesting that the two triploid lineages originated from separate triploidization events in Kāneʻohe Bay. The differentially expressed genes shared between these two triploid lineages, when compared to the diploid coral lineage, suggests changes in cellular physiology as a result of polyploidization. Functional analysis of the P. acuta genes can provide deeper insight into the specific, differentially regulated molecular functions and biological processes in triploids when compared to diploid P. acuta. Future studies involving comparative functional enrichment analysis with more triploid and diploid samples of P. acuta will provide more insight into events that caused triploidization and the coral’s response to environmental stressors.

Role of Nrf2 in aging, Alzheimer's and other neurodegenerative diseases.

Nuclear Factor-Erythroid Factor 2 (Nrf2) is an important transcription factor that regulates the expression of large number of genes in healthy and disease states. Nrf2 is made up of 605 amino acids and contains 7 conserved regions known as Nrf2-ECH homology domains. Nrf2 regulates the expression of several key components of oxidative stress, mitochondrial biogenesis, mitophagy, autophagy and mitochondrial function in all organs of the human body, in the peripheral and central nervous systems. Mounting evidence also suggests that altered expression of Nrf2 is largely involved in aging, neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's diseases, Amyotrophic lateral sclerosis, Stroke, Multiple sclerosis and others. The purpose of this article is to detail the essential role of Nrf2 in oxidative stress, antioxidative defense, detoxification, inflammatory responses, transcription factors, proteasomal and autophagic/mitophagic degradation, and metabolism in aging and neurodegenerative diseases. This article also highlights the Nrf2 structural and functional activities in healthy and disease states, and also discusses the current status of Nrf2 research and therapeutic strategies to treat aging and neurodegenerative diseases.

A New Technical Approach for Cross-species Examination of Neuronal Wiring and Adult Neuron-glia Functions

Advances in single cell sequencing have enabled the identification of a large number of genes, expressed in many different cell types, and across a variety of model organisms. In particular, the nervous system harbors an immense number of interacting cell types, which are poorly characterized. Future loss- and gain-of-function experiments will be essential in determining how novel genes play critical roles in diverse cellular, as well as evolutionarily adapted, contexts. However, functional analysis across species is often hampered by technical limitations, in non-genetic animal systems. Here, we describe a new single plasmid system, misPiggy. The system is based around the hyperactive piggyBac transposon system, which combines stable genomic integration of transgenes (for long-term expression) with large cargo capacity. Taking full advantage of these characteristics, we engineered novel expression modules into misPiggy that allow for cell-type specific loss- and gain-of-gene function. These modules work widely across species from frog to ferret. As a proof of principle, we present a loss-of-function analysis of the neuronal receptor Deleted in Colorectal Cancer (DCC) in retinal ganglion cells (RGCs) of Xenopus tropicalis tadpoles. Single axon tracings of mosaic knock-out cells reveal a specific cell-intrinsic requirement of DCC, specifically in axonal arborization within the frog tectum, rather than retina-to-brain axon guidance. Furthermore, we report additional technical advances that enable temporal control of knock-down or gain-of-function analysis. We applied this to visualize and manipulate labeled neurons, astrocytes and other glial cells in the central nervous system (CNS) of mouse, rat and ferret. We propose that misPiggy will be a valuable tool for rapid, flexible and cost-effective screening of gene function across a variety of animal models.

A Jasmonate-Responsive ERF Transcription Factor Regulates Steroidal Glycoalkaloid Biosynthesis Genes in Eggplant

Steroidal glycoalkaloids (SGAs) are a class of cholesterol-derived anti-nutritional defense compound that are produced in species of the genus Solanum, such as tomato (S. lycopersicum), potato (S. tuberosum), and eggplant (S. melongena). However, the regulation of defense-related metabolites in eggplant remains underexplored. In tomato and potato, the JASMONATE-RESPONSIVE ETHYLENE RESPONSE FACTOR 4 (JRE4) transcription factor positively regulates a large number of genes involved in SGA biosynthesis. Here, we report that the overexpression of eggplant JRE4 (SmJRE4) induces numerous metabolic genes involved in SGA biosynthesis in leaves. We demonstrate the jasmonate-dependent induction of SmJRE4 and its downstream metabolic genes and show that ethylene treatment attenuates this induction. Our findings thus provide molecular insights into SGA biosynthesis and its regulation in this major crop.

Astrocyte heterogeneity within white matter tracts and a unique subpopulation of optic nerve head astrocytes.

Much of what we know about astrocyte form and function is derived from the study of gray matter protoplasmic astrocytes, whereas white matter fibrous astrocytes remain relatively unexplored. Here, we used the ribotag approach to isolate ribosome-associated mRNA and investigated the transcriptome of uninjured fibrous astrocytes from three regions: unmyelinated optic nerve head, myelinated optic nerve proper, and corpus callosum. Astrocytes from each region were transcriptionally distinct and we identified region-specific astrocyte genes and pathways. Energy metabolism, particularly oxidative phosphorylation and mitochondrial protein translation emerged as key differentiators of astrocyte populations. Optic nerve astrocytes expressed higher levels of neuroinflammatory pathways than corpus callosum astrocytes and we further identified CARTPT as a new marker of optic nerve head astrocytes. These previously uncharacterized transcriptional profiles of white matter astrocyte types reveal their functional diversity and a greater heterogeneity than previously appreciated.

An association between copy number variation of enhancer involved in craniofacial development and biogeographic ancestry.

Human facial morphology is a combination of many complex traits and is determined by a large number of genes and enhancers. Here, we report a Copy Number Variation (CNV) study of enhancer hs1431 in populations of Central European and South Siberian ancestry. Central European samples included 97 Poles, while South Siberian samples included 78 Buryats and 27 Tuvinians. CNVs were detected by real-time PCR, using ViiA™ 7 Real-Time PCR System (Applied Biosystems). We revealed significant differences in CNV of hs1431 enhancer between Polish and Buryat population (p=0.0378), but not between Central European and South Siberian population (p=0.1225). Our results suggest that an increase in copy number variation of hs1431 enhancer is associated with biogeographic ancestry. However, this result needs extending and replicating in larger cohorts. This is the first study revealing the presence of copy number variation of enhancer hs1431 in humans.

Variability, Correlation and Path Analysis for Several Quantitative Traits Derived Multi-Parent Advanced Generation Inter-Cross (Magic) F2 Population of Rice (Oryza sativa L.)

Eight quantitative traits of an F2 MAGIC population in rice were subjected to analyze variability, correlation and path analysis. The results of third and fourth degree statistics (skewness and kurtosis) showed that Individual dried straw weight, 1000-seed weight, Individual grain yield, and Number of effective tillers are associated with complementary gene interaction, requiring intense selection, while Plant height, Panicle length, Spikelet fertility percentage, and Harvest index are associated with duplicate (additive x additive) gene interactions, are suitable for mild selection. Leptokurtic distribution of Plant height, Number of effective tillers per plant, Pancile length and Spikelet fertility percentage revealed that the large number of genes in governing the traits. Platykurtic distribution of Individual dried straw weight, 1000-seed weight, Individual grain yield and Harvest index indicated fewer genes controlling the traits. However, when it comes to H2 and GAM, high values were seen in Number of effective tillers per plant, Individual dried straw weight, Individual grain yield, the traits could be explained by additive gene action and achieved through mass selection. High heritability and lower GAM of Plant height, Panicle length, 1000-seed weight and Harvest index indicated by non-additive genes with limiting the chances of direct selection. For the Pearson correlation, 1000-seed weight showed no correlation with other traits. Individual grain yield highly correlated with Number of effective tillers per plant (0.864**) and Individual dried straw weight (0.828**). The highest total effects on Individual grain yield were Number of effective tillers per plant (2.7437) and Individual dried straw weight (1.0865). Individual dried straw weight had highest direct effect on Individual grain yield at 1.0734, while most of the traits showed high indirect effect on Individual grain yield through Individual dried straw weight.

Screening for eukaryotic motifs in Legionella pneumophila reveals Smh1 as bacterial deacetylase of host histones

ABSTRACT Legionella pneumophila (L.p.) is a bacterial pathogen which is a common causative agent of pneumonia. In humans, it infects alveolar macrophages and transfers hundreds of virulence factors that interfere with cellular signalling pathways and the transcriptomic landscape to sustain its own replication. By this interaction, it has acquired eukaryote-like protein motifs by gene transfer events that partake in the pathogenicity of Legionella. In a computational screening approach for eukaryotic motifs in the transcriptome of Legionella, we identified the L.p. strain Corby protein ABQ55614 as putative histone-deacetylase and named it “suppressing modifier of histones 1” (Smh1). During infection, Smh1 is translocated from the Legionella vacuole into the host cytosol. When expressed in human macrophage THP-1 cells, Smh1 was localized predominantly in the nucleus, leading to broad histone H3 and H4 deacetylation, blunted expression of a large number of genes (e.g. IL-1β and IL-8), and fostered intracellular bacterial replication. L.p. with a Smh1 knockdown grew normally in media but showed a slight growth defect inside the host cell. Furthermore, Smh1 showed a very potent histone deacetylation activity in vitro, e.g. at H3K14, that could be inhibited by targeted mutation of the putative catalytic center inferred by analogy with eukaryotic HDAC8, and with the deacetylase inhibitor trichostatin A. In summary, Smh1 displays functional homology with class I/II type HDACs. We identified Smh1 as a new Legionella virulence factor with a eukaryote-like histone-deacetylase activity that moderates host gene expression and might pave the way for further histone modifications. IMPORTANCE Legionella pneumophila (L.p.) is a prominent bacterial pathogen, which is a common causative agent of pneumonia. In order to survive inside the host cell, the human macrophage, it profoundly interacts with host cell processes to advance its own replication. In this study, we identify a bacterial factor, Smh1, with yet unknown function as a host histone deacetylase. The activity of this factor in the host cell leads to attenuated gene expression and increased intracellular bacterial replication.

A novel hybrid dimension reduction and deep learning-based classification for neuromuscular disorder

Correct classification of neuromuscular disorders is essential to provide accurate diagnosis. Presently, gene microarray technology is a widely accepted technology to monitor the expression level of a large number of genes simultaneously. The gene microarray data are a high dimensional data, which usually contains small samples having a large number of genes. Therefore, dimension reduction is a crucial task for correct classification of diseases. Dimension reduction eliminates those genes which are less expressive and enhances the efficiency of the classification model. In the present paper, we developed a novel hybrid dimension reduction method and a deep learning-based classification model for neuromuscular disorders. The hybrid dimension reduction method is deployed in three phase: in the first phase, the expressive genes are selected using F test method, and the mutual information method and the best one among them are selected for further processing. In second phase, the gene selected by the best model is further transformed to low dimension by PCA. In third phase, the deep learning-based classification model is deployed. For experimentation, two diseased and multi-diseased micro array data sets, which is publicly available, is used. The best accuracy by 50-100-50-25-13 deep learning architecture with hybrid dimension reduction, where 100 genes select by F test and PCA with 50 principal components is 89% for NMD data set. The best accuracy by 50-100-2 deep learning architecture with hybrid dimension reduction, where 100 genes select by F test and PCA with 50 principal components is 97% for FSHD data set. The proposed hybrid method gives better classification accuracy result and reduces the search space and time complexity as well for both two diseased and multi-diseased micro array data sets.

Frequent spontaneous structural rearrangements promote rapid genome diversification in a Brassica napus F1 generation.

In a cross between two homozygous Brassica napus plants of synthetic and natural origin, we demonstrate that novel structural genome variants from the synthetic parent cause immediate genome diversification among F1 offspring. Long read sequencing in twelve F1 sister plants revealed five large-scale structural rearrangements where both parents carried different homozygous alleles but the heterozygous F1 genomes were not identical heterozygotes as expected. Such spontaneous rearrangements were part of homoeologous exchanges or segmental deletions and were identified in different, individual F1 plants. The variants caused deletions, gene copy-number variations, diverging methylation patterns and other structural changes in large numbers of genes and may have been causal for unexpected phenotypic variation between individual F1 sister plants, for example strong divergence of plant height and leaf area. This example supports the hypothesis that spontaneous de novo structural rearrangements after de novo polyploidization can rapidly overcome intense allopolyploidization bottlenecks to re-expand crops genetic diversity for ecogeographical expansion and human selection. The findings imply that natural genome restructuring in allopolyploid plants from interspecific hybridization, a common approach in plant breeding, can have a considerably more drastic impact on genetic diversity in agricultural ecosystems than extremely precise, biotechnological genome modifications.

The inhibition of NCS-1 binding to Ric8a rescues fragile X syndrome mice model phenotypes

Fragile X syndrome (FXS) is caused by the loss of function of Fragile X mental retardation protein (FMRP). FXS is one of the leading monogenic causes of intellectual disability (ID) and autism. Although it is caused by the failure of a single gene, FMRP that functions as an RNA binding protein affects a large number of genes secondarily. All these genes represent hundreds of potential targets and different mechanisms that account for multiple pathological features, thereby hampering the search for effective treatments. In this scenario, it seems desirable to reorient therapies toward more general approaches. Neuronal calcium sensor 1 (NCS-1), through its interaction with the guanine-exchange factor Ric8a, regulates the number of synapses and the probability of the release of a neurotransmitter, the two neuronal features that are altered in FXS and other neurodevelopmental disorders. Inhibitors of the NCS-1/Ric8a complex have been shown to be effective in restoring abnormally high synapse numbers as well as improving associative learning in FMRP mutant flies. Here, we demonstrate that phenothiazine FD44, an NCS-1/Ric8a inhibitor, has strong inhibition ability in situ and sufficient bioavailability in the mouse brain. More importantly, administration of FD44 to two different FXS mouse models restores well-known FXS phenotypes, such as hyperactivity, associative learning, aggressive behavior, stereotype, or impaired social approach. It has been suggested that dopamine (DA) may play a relevant role in the behavior and in neurodevelopmental disorders in general. We have measured DA and its metabolites in different brain regions, finding a higher metabolic rate in the limbic area, which is also restored with FD44 treatment. Therefore, in addition to confirming that the NCS-1/Ric8a complex is an excellent therapeutic target, we demonstrate the rescue effect of its inhibitor on the behavior of cognitive and autistic FXS mice and show DA metabolism as a FXS biochemical disease marker.