Modeling Rett Syndrome Using TALEN-Edited MECP2 Mutant Cynomolgus Monkeys.

Gene-editing technologies have made it feasible to create nonhuman primate models for human genetic disorders. Here, we report detailed genotypes and phenotypes of TALEN-edited MECP2 mutant cynomolgus monkeys serving as a model for a neurodevelopmental disorder, Rett syndrome (RTT), which is caused by loss-of-function mutations in the human MECP2 gene. Male mutant monkeys were embryonic lethal, reiterating that RTT is a disease of females. Through a battery of behavioral analyses, including primate-unique eye-tracking tests, in combination with brain imaging via MRI, we found a series of physiological, behavioral, and structural abnormalities resembling clinical manifestations of RTT. Moreover, blood transcriptome profiling revealed that mutant monkeys resembled RTT patients in immune gene dysregulation. Taken together, the stark similarity in phenotype and/or endophenotype between monkeys and patients suggested that gene-edited RTT founder monkeys would be of value for disease mechanistic studies as well as development of potential therapeutic interventions for RTT.

Single-cell transcriptome analyses reveal signals to activate dormant neural stem cells.

The scarcity of tissue-specific stem cells and the complexity of their surrounding environment have made molecular characterization of these cells particularly challenging. Through single-cell transcriptome and weighted gene co-expression network analysis (WGCNA), we uncovered molecular properties of CD133(+)/GFAP(-) ependymal (E) cells in the adult mouse forebrain neurogenic zone. Surprisingly, prominent hub genes of the gene network unique to ependymal CD133(+)/GFAP(-) quiescent cells were enriched for immune-responsive genes, as well as genes encoding receptors for angiogenic factors. Administration of vascular endothelial growth factor (VEGF) activated CD133(+) ependymal neural stem cells (NSCs), lining not only the lateral but also the fourth ventricles and, together with basic fibroblast growth factor (bFGF), elicited subsequent neural lineage differentiation and migration. This study revealed the existence of dormant ependymal NSCs throughout the ventricular surface of the CNS, as well as signals abundant after injury for their activation.

Trideuteromethylthiolation through Reaction of Arynes, S-Methyl-d3 Sulfonothioate with Sulfonamides or Amides: Access to Trideuteromethylated Sulfilimines.

A direct and practical three-component tandem reaction of arynes, S-methyl-d3 sulfonothioate with sulfonamides or amides is developed. The reaction is highly efficient and chemoselective, which allows mild synthesis of trideuteromethylated sulfilimines with broad substrate scope and good functional group compatibility, giving the products in good to excellent yields with 92%-99% deuterium incorporation. Mechanism studies disclosed sulfenamide that generated in situ is the key intermediate for the reaction. This protocol provides potential method for introduction of -SCD3 moiety for deuteration of marked drugs and drug candidates containing sulfilimine skeleton.

Polyphenol Profile, Antioxidant Activity, and Hypolipidemic Effect of Longan Byproducts.

Longan, a popular fruit in Asia, has been used in traditional Chinese medicine to treat several diseases for centuries. Recent studies have indicated that longan byproducts are rich in polyphenols. The aim of this study was to analyze the phenolic composition of longan byproduct polyphenol extracts (LPPE), evaluate their antioxidant activity in vitro, and investigate their regulating effect on lipid metabolism in vivo. The results indicated that the antioxidant activity of LPPE was 231.350 ± 21.640, 252.380 ± 31.150, and 558.220 ± 59.810 (mg Vc/g) as determined by DPPH, ABTS, and FRAP, respectively. UPLC-QqQ-MS/MS analysis indicated that the main compounds in LPPE were gallic acid, proanthocyanidin, epicatechin, and phlorizin. LPPE supplementation prevented the body weight gain and decreased serum and liver lipids in high-fat diet-induced-obese mice. Furthermore, RT-PCR and Western blot analysis indicated that LPPE upregulated the expression of PPARα and LXRα and then regulated their target genes, including FAS, CYP7A1, and CYP27A1, which are involved in lipid homeostasis. Taken together, this study supports the concept that LPPE can be used as a dietary supplement in regulating lipid metabolism.

Natural antisense RNA Foxk1-AS promotes myogenic differentiation by inhibiting Foxk1 activity.

BACKGROUND: Natural antisense RNAs are RNA molecules that are transcribed from the opposite strand of either protein-coding or non-protein coding genes and have the ability to regulate the expression of their sense gene or several related genes. However, the roles of natural antisense RNAs in the maintenance and myogenesis of muscle stem cells remain largely unexamined. METHODS: We analysed myoblast differentiation and regeneration by overexpression and knockdown of Foxk1-AS using lentivirus and adeno-associated virus infection in C2C12 cells and damaged muscle tissues. Muscle injury was induced by BaCl2 and the regeneration and repair of damaged muscle tissues was assessed by haematoxylin-eosin staining and quantitative real-time PCR. The expression of myogenic differentiation-related genes was verified via quantitative real-time PCR, Western blotting and immunofluorescence staining. RESULTS: We identified a novel natural antisense RNA, Foxk1-AS, which is transcribed from the opposite strand of Foxk1 DNA and completely incorporated in the 3' UTR of Foxk1. Foxk1-AS targets Foxk1 and functions as a regulator of myogenesis. Overexpression of Foxk1-AS strongly inhibited the expression of Foxk1 in C2C12 cells and in tibialis anterior muscle tissue and promoted myoblast differentiation and the regeneration of muscle fibres damaged by BaCl2. Furthermore, overexpression of Foxk1-AS promoted the expression of Mef2c, which is an important transcription factor in the control of muscle gene expression and is negatively regulated by Foxk1. CONCLUSION: The results indicated that Foxk1-AS represses Foxk1, thereby rescuing Mef2c activity and promoting myogenic differentiation of C2C12 cells and regeneration of damaged muscle fibres. Video Abstract.

Identification of Immune Cells and Key Genes associated with Alzheimer's Disease.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by cognitive impairment and memory loss, for which there is no effective cure to date. In the past several years, numerous studies have shown that increased inflammation in AD is a major cause of cognitive impairment. This study aimed to reveal 22 kinds of peripheral immune cell types and key genes associated with AD. The prefrontal cortex transcriptomic data from Gene Expression Omnibus (GEO) database were collected, and CIBERSORT was used to assess the composition of 22 kinds of immune cells in all samples. Weighted gene co-expression network analysis (WGCNA) was used to construct gene co-expression networks and identified candidate module genes associated with AD. The least absolute shrinkage and selection operator (LASSO) and random forest (RF) models were constructed to analyze candidate module genes, which were selected from the result of WGCNA. The results showed that the immune infiltration in the prefrontal cortex of AD patients was different from healthy samples. Of all 22 kinds of immune cells, M1 macrophages were the most relevant cell type to AD. We revealed 10 key genes associated with AD and M1 macrophages by LASSO and RF analysis, including ARMCX5, EDN3, GPR174, MRPL23, RAET1E, ROD1, TRAF1, WNT7B, OR4K2 and ZNF543. We verified these 10 genes by logistic regression and k-fold cross-validation. We also validated the key genes in an independent dataset, and found GPR174, TRAF1, ROD1, RAET1E, OR4K2, MRPL23, ARMCX5 and EDN3 were significantly different between the AD and healthy controls. Moreover, in the 5XFAD transgenic mice, the differential expression trends of Wnt7b, Gpr174, Ptbp3, Mrpl23, Armcx5 and Raet1e are consistent with them in independent dataset. Our results provided potential therapeutic targets for AD patients.

Transition metals and metal complexes in autophagy and diseases.

Transition metals refer to the elements in the d and ds blocks of the periodic table. Since the success of cisplatin and auranofin, transition metal-based compounds have become a prospective source for drug development, particularly in cancer treatment. In recent years, extensive studies have shown that numerous transition metal-based compounds could modulate autophagy, promising a new therapeutic strategy for metal-related diseases and the design of metal-based agents. Copper, zinc, and manganese, which are common components in physiological pathways, play important roles in the progression of cancer, neurodegenerative diseases, and cardiovascular diseases. Furthermore, enrichment of copper, zinc, or manganese can regulate autophagy. Thus, we summarized the current advances in elucidating the mechanisms of some metals/metal-based compounds and their functions in autophagy regulation, which is conducive to explore the intricate roles of autophagy and exploit novel therapeutic drugs for human diseases.

Triptolide impairs glycolysis by suppressing GATA4/Sp1/PFKP signaling axis in mouse Sertoli cells.

Triptolide (TP), a primary bioactive ingredient isolated from the traditional Chinese herbal medicine Tripterygium wilfordii Hook. F. (TWHF), has attracted great interest for its therapeutic biological activities in inflammation and autoimmune disease. However, its clinical use is limited by severe testicular toxicity, and the underlying mechanism has not been elucidated. Our preliminary evidence demonstrated that TP disrupted glucose metabolism and caused testicular toxicity. During spermatogenesis, Sertoli cells (SCs) provide lactate as an energy source to germ cells by glycolysis. The transcription factors GATA-binding protein 4 (GATA4) and specificity protein 1 (Sp1) can regulate glycolysis. Based on this evidence, we speculate that TP causes abnormal glycolysis in SCs by influencing the expression of the transcription factors GATA4 and Sp1. The mechanism of TP-induced testicular toxicity was investigated in vitro and in vivo. The data indicated that TP decreased glucose consumption, lactate production, and the mRNA levels of glycolysis-related transporters and enzymes. TP also downregulated the protein expression of the transcription factors GATA4 and Sp1, as well as the glycolytic enzyme phosphofructokinase platelet (PFKP). Phosphorylated GATA4 and nuclear GATA4 protein levels were reduced in a dose- and time-dependent manner after TP incubation. Similar effects were observed in shGata4-treated TM4 cells and BALB/c mice administered 0.4 mg/kg TP for 28 days, and glycolysis was also inhibited. Gata4 knockdown downregulated Sp1 and PFKP expression. Furthermore, the Sp1 inhibitor plicamycin inhibited PFKP protein levels in TM4 cells. In conclusion, TP inhibited GATA4-mediated glycolysis by suppressing Sp1-dependent PFKP expression in SCs and caused testicular toxicity.

Lipid Metabolism is the common pathologic mechanism between Type 2 Diabetes Mellitus and Parkinson's disease.

Although increasing evidence has suggested crosstalk between Parkinson's disease (PD) and type 2 diabetes mellitus (T2DM), the common mechanisms between the two diseases remain unclear. The aim of our study was to characterize the interconnection between T2DM and PD by exploring their shared biological pathways and convergent molecules. The intersections among the differentially expressed genes (DEGs) in the T2DM dataset GSE95849 and PD dataset GSE6613 from the Gene Expression Omnibus (GEO) database were identified as the communal DEGs between the two diseases. Then, an enrichment analysis, protein-protein interaction (PPI) network analysis, correlation analysis, and transcription factor-target regulatory network analysis were performed for the communal DEGs. As a result, 113 communal DEGs were found between PD and T2DM. They were enriched in lipid metabolism, including protein modifications that regulate metabolism, lipid synthesis and decomposition, and the biological effects of lipid products. All these pathways and their biological processes play important roles in both diseases. Fifteen hub genes identified from the PPI network could be core molecules. Their function annotations also focused on lipid metabolism. According to the correlation analysis and the regulatory network analysis based on the 15 hub genes, Sp1 transcription factor (SP1) could be a key molecule since it affected other hub genes that participate in the common mechanisms between PD and T2DM. In conclusion, our analyses reveal that changes in lipid metabolism could be a key intersection between PD and T2DM, and that SP1 could be a key molecule regulating these processes. Our findings provide novel points for the association between PD and T2DM.

Conservation and divergence of transcriptional coregulations between box C/D snoRNA and ribosomal protein genes in Ascomycota.

Coordinated assembly of the ribosome is essential for proper translational activity in eukaryotic cells. It is therefore critical to coordinate the expression of components of ribosomal programs with the cell's nutritional status. However, coordinating expression of these components is poorly understood. Here, by combining experimental and computational approaches, we systematically identified box C/D snoRNAs in four fission yeasts and found that the expression of box C/D snoRNA and ribosomal protein (RP) genes were orchestrated by a common Homol-D box, thereby ensuring a constant balance of these two genetic components. Interestingly, such transcriptional coregulations could be observed in most Ascomycota species and were mediated by different cis-regulatory elements. Via the reservation of cis elements, changes in spatial configuration, the substitution of cis elements, and gain or loss of cis elements, the regulatory networks of box C/D snoRNAs evolved to correspond with those of the RP genes, maintaining transcriptional coregulation between box C/D snoRNAs and RP genes. Our results indicate that coregulation via common cis elements is an important mechanism to coordinate expression of the RP and snoRNA genes, which ensures a constant balance of these two components.

Generation of Human Embryonic Stem Cell Line Expressing zsGreen in Cholinergic Neurons Using CRISPR/Cas9 System.

Lineage specific human embryonic stem cell (hESC) reporter cell line is a versatile tool for biological studies on real time monitoring of differentiation, physiological and biochemical features of special cell types and pathological mechanism of disease. Here we report the generation of ChAT-zsGreen reporter hESC line that express zsGreen under the control of the choline acetyltransferase (ChAT) promoter using CRISPR (Clustered Regularly Interspersed Short Palindromic Repeats)/Cas9 system. We show that the ChAT-zsGreen hESC reporter cell lines retain the features of undifferentiated hESC. After cholinergic neuronal differentiation, cholinergic neurons were clearly labeled with green fluorescence protein (zsGreen). The ChAT-zsGreen reporter hESC lines are invaluable not only for the monitoring cholinergic neuronal differentiation but also for study physiological and biochemical hallmarks of cholinergic neurons.

Computational identification and experimental validation of microRNAs binding to the fragile X syndrome gene Fmr1.

MicroRNAs (miRNAs) usually bind to their target mRNAs through imperfect base pairing in the 3'-untranslated regions (3' UTRs) and regulate target gene expression via post-transcriptional suppression. In recent years, computational approaches to predict miRNA targets have facilitated the identification of potential target sites. In this study, we used three programs TargetScan, miRDB and miRanda to predict potential miRNA binding sites to the fragile X gene Fmr1 and picked out 61 miRNAs which were predicted by all three programs for further investigation. Excitingly, 5 out of these miRNAs, miR-23a, miR-32, miR-124, miR-335-5p and miR-350, were experimentally verified by luciferase reporter assays. Furthermore, overexpression of miR-124 in mouse embryonic neural progenitor cells (eNPC) could not only significantly reduce Fmr1 level, but also increase Cdk4 and cyclin D1 levels which coincidently promoted eNPC proliferation. Our results imply that miR-124 plays an important role in the proliferation of mouse embryonic stem cells by promoting Cdk4 and cyclin D1 expression through directly inhibiting Fmr1 expression.

Identification and functional analysis of long non-coding RNAs in mouse cleavage stage embryonic development based on single cell transcriptome data.

BACKGROUND: Long non-coding RNAs (lncRNAs) regulate embryonic development and cell fate decision in various ways, such as modulation of chromatin modification and post-transcription regulation of gene expression. However, the profiles and roles of lncRNAs in early mammalian development have not yet been demonstrated. Here, we reported a comprehensive analysis of mouse cleavage stage embryonic lncRNA profiles based on public single-cell RNA-seq data. RESULTS: We reconstructed 50,006 high-confidence transcripts in 22,827 loci, and identified 5563 novel lncRNAs from 3492 loci expressed in mouse cleavage stage embryos. These lncRNAs share similar characteristics with previously reported vertebrate lncRNAs, such as relatively short length, low exon number, low expression level and low sequence conservation. Expression profile analysis revealed that the profiles of lncRNA vary considerably at different stages of cleavage stage embryos, suggesting that many lncRNAs in cleavage stage embryos are stage-specifically expressed. Co-expression network analysis suggested many lncRNAs in cleavage stage embryos are associated with cell cycle regulation, transcription, translation and oxidative phosphorylation to regulate the process of cleavage stage embryonic development. CONCLUSIONS: This study provides the first catalog of lncRNAs expressed in mouse cleavage stage embryos and gives a revealing insight into the molecular mechanism responsible for early embryonic development.

The roles of neural stem cells in myelin regeneration and repair therapy after spinal cord injury.

Spinal cord injury (SCI) is a complex tissue injury that results in a wide range of physical deficits, including permanent or progressive disabilities of sensory, motor and autonomic functions. To date, limitations in current clinical treatment options can leave SCI patients with lifelong disabilities. There is an urgent need to develop new therapies for reconstructing the damaged spinal cord neuron-glia network and restoring connectivity with the supraspinal pathways. Neural stem cells (NSCs) possess the ability to self-renew and differentiate into neurons and neuroglia, including oligodendrocytes, which are cells responsible for the formation and maintenance of the myelin sheath and the regeneration of demyelinated axons. For these properties, NSCs are considered to be a promising cell source for rebuilding damaged neural circuits and promoting myelin regeneration. Over the past decade, transplantation of NSCs has been extensively tested in a variety of preclinical models of SCI. This review aims to highlight the pathophysiology of SCI and promote the understanding of the role of NSCs in SCI repair therapy and the current advances in pathological mechanism, pre-clinical studies, as well as clinical trials of SCI via NSC transplantation therapeutic strategy. Understanding and mastering these frontier updates will pave the way for establishing novel therapeutic strategies to improve the quality of recovery from SCI.

Unraveling the role of Major Vault Protein as a novel immune-related biomarker that promotes the proliferation and migration in pancreatic adenocarcinoma.

Background: Pancreatic adenocarcinoma (PAAD) is a formidable challenge in oncology research, with a complex pathogenesis that requires to be explored. Major Vault Protein (MVP) is the principal structural component of the vault complex, and its expression level is remarkably upregulated in various cancers. Extensive investigations have been conducted to explore the role of MVP in specific cancer contexts, yet the potential molecular mechanisms and biological functions of MVP in PAAD still remain considerably elusive. This study aims to explore the role of MVP as a novel immune-related biomarker in the pathogenesis and clinical treatment of PAAD. Methods: Gene expression data and clinical information were collected from TCGA, GTEx and GEO databases. Survival, prognostic and functional enrichment analysis were employed with R software. Immunological correlation analysis was performed using TIMER2.0, TIDE scores, TISIDB and TISCH. Epigenetic analysis was implemented by MethSurv, CPTAC, UALCAN, and cBioPortal. Drug analysis was conducted using Enrichr and CellMiner. Moreover, cellular experiments, like RNA interference, qRT-PCR, Western blot, cell cycle analysis, cell apoptosis analysis, colony formation assay, transwell assay, and wound healing assay, were performed for verifying the functional properties of MVP in the PAAD progression. Results: We demonstrated an abnormally upregulated expression of MVP in PAAD tissues, which notably correlated with an adverse prognosis in PAAD patients. Functional analysis suggested the conceivable involvement of MVP in immune modulation, and immunotherapy. Additionally, we identified genetic alterations, reduced promoter methylation, and heightened phosphorylation in MVP. We also clarified Suloctidil and Tetradioxin as the most notable potential drugs targeting MVP in PAAD. Moreover, our experimental observations consistently highlighted the significant impact of MVP deficiency on impeding PAAD cell proliferation, inhibiting cell migration, and accelerating cell apoptosis. Interestingly, a potential link between MVP and ERK or AKT pathways was displayed, which opens new avenues for further exploration of the molecular mechanisms of MVP-targeted therapies in PAAD. Conclusions: This study systematically describes MVP as an immune-related biomarker with remarkable potential for predicting the prognosis, tumor progression and immunotherapeutic efficacy in PAAD.

Co-hydrothermal carbonization of lignocellulosic biomass and swine manure: Optimal parameters for enhanced nutrient reclamation, carbon sequestration, and heavy metals passivation.

Hydrochar, the primary product of hydrothermal carbonization (HTC) of wet organic waste, is recognized as a versatile, carbon-abundant material with diverse applications. However, optimizing its performance for specific uses remains challenging. Therefore, this study introduced a co-HTC process involving carbon-rich lignocellulosic materials and ash-rich livestock manure [i.e., Zanthoxylum bungeanum branch residue (ZB) and swine manure (SM), respectively]. The impacts of HTC temperature (i.e., 180 °C, 220 °C, and 240 °C) and mass ratios (i.e., 1:0, 7:3, 5:5, 3:7, and 0:1) on hydrochar properties (e.g., pH, EC, nutrient contents, heavy metal content and availability, chemical stability, etc) and the characteristics of process water were evaluated. Results reveal that co-HTC dramatically improved the quality of hydrochars compared with that derived from a single feedstock. Notably, the ZB:SM ratio had a more substantial impact on total nutrient content, carbon stability, and heavy metal accumulation and mobility. Additionally, the synergistic effects of ZB and SM were greatly dependent on the HTC temperature. By adjusting the feedstock mass ratio and HTC temperature, a highly-functionalized hydrochar can be produced. For example, hydrochars produced at 240 °C with a 7:3 ZB to SM ratio (HC240-7) is optimal for degraded soil amendment, enhancing carbon sequestration and nutrient supplementation. Results from this study could provide valuable insights for improving waste management through HTC and expanding the environmental and agricultural application of hydrochar.

Characteristics of quiescent adult neural stem cells induced by the bFGF/BMP4 combination or BMP4 alone in vitro.

Bone morphogenetic protein-4 (BMP4) is involved in regulation of neural stem cells (NSCs) proliferation, differentiation, migration and survival. It was previously thought that the treatment of NSCs with BMP4 alone induces astrocytes, whereas the treatment of NSCs with the bFGF/BMP4 combination induces quiescent neural stem cells (qNSCs). In this study, we performed bulk RNA sequencing (RNA-Seq) to compare the transcriptome profiles of BMP4-treated NSCs and bFGF/BMP4-treated NSCs, and found that both NSCs treated by these two methods were Sox2 positive qNSCs which were able to generate neurospheres. However, NSCs treated by those two methods exhibited different characteristics in state and the potential for neuronal differentiation based on transcriptome analysis and experimental results. We found that BMP4-treated NSCs tended to be in a deeper quiescent state than bFGF/BMP4-treated NSCs as the percentage of ki67-positive cells were lower in BMP4-treated NSCs. And after exposure to differentiated environment, bFGF/BMP4-treated NSCs generated more DCX-positive immature neurons and MAP2-positive neurons than BMP4-treated NSCs. Our study characterized qNSCs treated with BMP4 alone and bFGF/BMP4 combination, providing a reference for the scientific use of BMP4 and bFGF/BMP4-induced qNSCs models.

VEGF-FGF Signaling Activates Quiescent CD63+ Liver Stem Cells to Proliferate and Differentiate.

Understanding the liver stem cells (LSCs) holds great promise for new insights into liver diseases and liver regeneration. However, the heterogenicity and plasticity of liver cells have made it controversial. Here, by employing single-cell RNA-sequencing technology, transcriptome features of Krt19+ bile duct lineage cells isolated from Krt19CreERT; Rosa26R-GFP reporter mouse livers are examined. Distinct biliary epithelial cells which include adult LSCs, as well as their downstream hepatocytes and cholangiocytes are identified. Importantly, a novel cell surface LSCs marker, CD63, as well as CD56, which distinguished active and quiescent LSCs are discovered. Cell expansion and bi-potential differentiation in culture demonstrate the stemness ability of CD63+ cells in vitro. Transplantation and lineage tracing of CD63+ cells confirm their contribution to liver cell mass in vivo upon injury. Moreover, CD63+CD56+ cells are proved to be activated LSCs with vigorous proliferation ability. Further studies confirm that CD63+CD56- quiescent LSCs express VEGFR2 and FGFR1, and they can be activated to proliferation and differentiation through combination of growth factors: VEGF-A and bFGF. These findings define an authentic adult liver stem cells compartment, make a further understanding of fate regulation on LSCs, and highlight its contribution to liver during pathophysiologic processes.

MicroRNA-130b targets Fmr1 and regulates embryonic neural progenitor cell proliferation and differentiation.

Fragile X syndrome, one of the most common forms of inherited mental retardation, is caused by expansion of the CGG repeat in the 5'-untranslated region of the X-linked Fmr1 gene, which results in transcriptional silencing and loss of expression of its encoded protein FMRP. The loss of FMRP increases proliferation and alters fate specification in adult neural progenitor cells (aNPCs). However, little is known about Fmr1 mRNA regulation at the transcriptional and post-transcriptional levels. In the present study, we report that miR-130b regulated Fmr1 expression by directly targeting its 3'-untranslated region (3' UTR). Up-regulation of miR-130b in mouse embryonic neural progenitor cells (eNPCs) decreased Fmr1 expression, markedly increased eNPC proliferation and altered the differentiation tendency of eNPCs, suggesting that antagonizing miR-130b may be a new therapeutic entry point for treating Fragile X syndrome.

Fragile x mental retardation protein regulates proliferation and differentiation of adult neural stem/progenitor cells.

Fragile X syndrome (FXS), the most common form of inherited mental retardation, is caused by the loss of functional fragile X mental retardation protein (FMRP). FMRP is an RNA-binding protein that can regulate the translation of specific mRNAs. Adult neurogenesis, a process considered important for neuroplasticity and memory, is regulated at multiple molecular levels. In this study, we investigated whether Fmrp deficiency affects adult neurogenesis. We show that in a mouse model of fragile X syndrome, adult neurogenesis is indeed altered. The loss of Fmrp increases the proliferation and alters the fate specification of adult neural progenitor/stem cells (aNPCs). We demonstrate that Fmrp regulates the protein expression of several components critical for aNPC function, including CDK4 and GSK3beta. Dysregulation of GSK3beta led to reduced Wnt signaling pathway activity, which altered the expression of neurogenin1 and the fate specification of aNPCs. These data unveil a novel regulatory role for Fmrp and translational regulation in adult neurogenesis.