Deletion of Schizophrenia Susceptibility Gene Ulk4 Leads to Abnormal Cognitive Behaviors via Akt-GSK-3 Signaling Pathway in Mice.

OBJECTIVES: Despite of strenuous research in the past decades, the etiology of schizophrenia (SCZ) still remains incredibly controversial. Previous genetic analysis has uncovered a close association of Unc-51 like kinase 4 (ULK4), a family member of Unc-51-like serine/threonine kinase, with SCZ. However, animal behavior data which may connect Ulk4 deficiency with psychiatric disorders, particularly SCZ are still missing. METHODS: We generated Emx1-Cre:Ulk4flox/flox conditional knockout (CKO) mice, in which Ulk4 was deleted in the excitatory neurons of cerebral cortex and hippocampus. RESULTS: The cerebral cellular architecture was maintained but the spine density of pyramidal neurons was reduced in Ulk4 CKO mice. CKO mice showed deficits in the spatial and working memories and sensorimotor gating. Levels of p-Akt and p-GSK-3α/ß were markedly reduced in the CKO mice indicating an elevation of GSK-3 signaling. Mechanistically, Ulk4 may regulate the GSK-3 signaling via putative protein complex comprising of two phosphatases, protein phosphatase 2A (PP2A) and 1α (PP1α). Indeed, the reduction of p-Akt and p-GSK-3α/ß was rescued by administration of inhibitor acting on PP2A and PP1α in CKO mice. CONCLUSIONS: Our data identified potential downstream signaling pathway of Ulk4, which plays important roles in the cognitive functions and when defective, may promote SCZ-like pathogenesis and behavioral phenotypes in mice.

A patient with femoral osteitis fibrosa cystica mimicking bone neoplasm: a case report.

BACKGROUND: Osteitis fibrosa cystica is a rare, benign and osteolytic lesion attributed to hyperparathyroidism. The high level of parathyroid hormone cause rapid bone loss. CASE PRESENTATION: The patient is a 50-year-old male complaining of severe and persistent pain in the right knee joint. Imaging studies were suspicious for a benign tumor in the right distal femur. Biopsy under CT guidance showed numerous osteoclast aggregation and hemosiderin deposition around the bone trabeculae. Blood tests disclosed significantly elevated parathyroid hormone, serum calcium, serum alkaline phosphatase. Parathyroid ultrasonography and CT scan showed a solid mass in front of the trachea at the thoracic entrance plane. After resection of the mass, the clinical symptoms were relieved and the radiological results were significantly improved, which further confirmed the diagnosis. CONCLUSIONS: Metabolic diseases-associated bone lesions require a comprehensive diagnosis of multiple inspection items. An interprofessional team approach to the diagnosis and treatment of osteitis fibrosa cystica will provide the best outcome.

Ulk4, a Newly Discovered Susceptibility Gene for Schizophrenia, Regulates Corticogenesis in Mice.

Schizophrenia (SCZ) is a chronic and severe mental disease that affects around 1% of the population. The precise etiology of SCZ still remains largely unknown, and no conclusive mechanisms are firmly established. Recent advances in epidemiological and clinical investigation support an overwhelmingly strong neurodevelopmental origin for SCZ. Here, we demonstrated that Unc-51-like kinase 4 (Ulk4), a novel risk factor for major mental disorders including schizophrenia, is involved in the corticogenesis. Deletion of Ulk4 in mice led to significantly thinner layers of II-III, and V in the cerebral cortex, which was confirmed in conditional Ulk4 deletion mice achieved by Cre-loxp strategy. This abnormality might be caused by decreased intermediate neural progenitors and increased apoptosis. Thus, our data suggest that Ulk4 manipulates the behaviors of neural progenitors during brain development and, when functionally defective, leads to the reduction of specific cortical layers. This anomaly may increase predisposition to a range of neurodevelopmental disorders, including SCZ.

Pten is a key intrinsic factor regulating raphe 5-HT neuronal plasticity and depressive behaviors in mice.

Serotonin (5-HT)-based antidepressants, selective serotonin reuptake inhibitors (SSRIs) aim to enhance serotonergic activity by blocking its reuptake. We propose PTEN as a target for an alternative approach for regulating 5-HT neuron activity in the brain and depressive behaviors. We show that PTEN is elevated in central 5-HT neurons in the raphe nucleus by chronic stress in mice, and selective deletion of Pten in the 5-HT neurons induces its structural plasticity shown by increases of dendritic branching and density of PSD95-positive puncta in the dendrites. 5-HT levels are elevated and electrical stimulation of raphe neurons evokes more 5-HT release in the brain of condition knockout (cKO) mice with Pten-deficient 5-HT neurons. In addition, the 5-HT neurons remain normal electrophysiological properties but have increased excitatory synaptic inputs. Single-cell RNA sequencing revealed gene transcript alterations that may underlay morphological and functional changes in Pten-deficient 5-HT neurons. Finally, Pten cKO mice and wild-type mice treated with systemic application of PTEN inhibitor display reduced depression-like behaviors. Thus, PTEN is an intrinsic regulator of 5-HT neuron activity, representing a novel therapeutic strategy for producing antidepressant action.

[A Review of High-altitude Hypoxia Adaptation and Hypoxic Solid Tumor].

Historically, the Cambrian explosion was a major life evolution event caused by changes of natural environmental oxygen concentration. The use of oxygen was part of the basic survival instinct of higher life, which evolved a complex regulation system in response to variant levels of oxygen concentration. Hypoxia is one of the typical environmental characteristics in plateau areas. After long-term natural selection in hypoxic conditions, numerous species living in plateau areas have evolved unique mechanisms adapted to hypoxia. Recent studies have found that there are some similarities in adaptation to hypoxia between the animals in highland and different types of human solid tumor cells. Herein, we will summarize recent findings about the hypoxia adaptation evolution in high-altitude animals and the characteristics of hypoxic solid tumors, especially the reactive oxygen species responses in hypoxic solid tumors. We believe that deciphering the underlying molecular mechanisms involved in hypoxia adaptation in highland will facilitate the identification of new genes or biomarkers critical for research on hypoxic solid tumors in the future.

ZFP804A mutant mice display sex-dependent schizophrenia-like behaviors.

Genome-wide association studies uncovered the association of ZNF804A (Zinc-finger protein 804A) with schizophrenia (SZ). In vitro data have indicated that ZNF804A might exert its biological roles by regulating spine and neurite morphogenesis. However, no in vivo data are available for the role of ZNF804A in psychiatric disorders in general, SZ in particular. We generated ZFP804A mutant mice, and they showed deficits in contextual fear and spatial memory. We also observed the sensorimotor gating impairment, as revealed by the prepulse inhibition test, but only in female ZFP804A mutant mice from the age of 6 months. Notably, the PPI difference between the female mutant and control mice was no longer existed with the administration of Clozapine or after the ovariectomy. Hippocampal long-term potentiation was normal in both genders of the mutant mice. Long-term depression was absent in male mutants, but facilitated in the female mutants. Protein levels of hippocampal serotonin-6 receptor and GABAB1 receptor were increased, while those of cortical dopamine 2 receptor were decreased in the female mutants with no obvious changes in the male mutants. Moreover, the spine density was reduced in the cerebral cortex and hippocampus of the mutant mice. Knockdown of ZFP804A impaired the neurite morphogenesis of cortical and hippocampal neurons, while its overexpression enhanced neurite morphogenesis only in the cortical neurons in vitro. Our data collectively support the idea that ZFP804A/ZNF804A plays important roles in the cognitive functions and sensorimotor gating, and its dysfunction may contribute to SZ, particularly in the female patients.

Giant Cell-Rich Solitary Fibrous Tumor in the Nasopharynx: Case Report and Literature Review.

Solitary fibrous tumors (SFTs) can occur in several locations outside the pleura, but rarely in the sinonasal tract, and particularly not in the nasopharynx. Herein, we describe an unusual case of giant cell-rich SFT (GCRSFT) occurring in the nasopharynx. A 64-year-old man experienced dizziness and headache for more than 10 years with no obvious cause. Computed tomography (CT) scan showed a 3.9 cm × 2 cm tumor on the posterior lateral wall of the left nasopharynx, and angiography revealed a hypervascular tumor fed by branches of the left carotid artery. Hence, preoperative embolization was performed, and then the tumor was endoscopically resected. The symptoms were relieved after the resection, and postoperative head CT and video laryngoscopy showed that the tumor was completely resected. We next characterized the specific pathological characteristics of the resected tumor. Histologically, the tumor was characterized by varying cellular proliferation of cytologically bland spindle cells within a collagenous stroma, with prominent interspersed branching vessels. Mitotic activity was low (2/50HPF), and there was no evidence of pleomorphism or tumor necrosis. Moreover, multinucleated giant cells with deep nuclear staining and distributed in pseudovascular spaces were found within the tumor. We ruled out the possibility that our case was giant cell fibroblastoma (GCF) by immunohistochemical analysis, showing that the tumor cells were positive for CD34, CD99, STAT6, and BCL-2, and that the Ki-67 labeling index was 3%, indicating that our case was SFT and not GCF. The patient's condition is generally good after a 14-month follow-up. This report serves to broaden the morphologic spectrum of GCRSFT and will help clinicians and pathologists better understand this entity to prevent misdiagnosis.

Convergent genomic signatures of high-altitude adaptation among domestic mammals.

Abundant and diverse domestic mammals living on the Tibetan Plateau provide useful materials for investigating adaptive evolution and genetic convergence. Here, we used 327 genomes from horses, sheep, goats, cattle, pigs and dogs living at both high and low altitudes, including 73 genomes generated for this study, to disentangle the genetic mechanisms underlying local adaptation of domestic mammals. Although molecular convergence is comparatively rare at the DNA sequence level, we found convergent signature of positive selection at the gene level, particularly the EPAS1 gene in these Tibetan domestic mammals. We also reported a potential function in response to hypoxia for the gene C10orf67, which underwent positive selection in three of the domestic mammals. Our data provide an insight into adaptive evolution of high-altitude domestic mammals, and should facilitate the search for additional novel genes involved in the hypoxia response pathway.

Author Correction: Comprehensive integrative analyses identify GLT8D1 and CSNK2B as schizophrenia risk genes.

In the original version of this Article, the affiliation details for Qiushuo Shen incorrectly omitted 'Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, 650204, China'. This has now been corrected in both the PDF and HTML versions of the Article.

Transcriptome profiling of rubber tree (Hevea brasiliensis) discovers candidate regulators of the cold stress response.

Tropical plant rubber tree (Hevea brasiliensis) is the sole source of commercial natural rubber and low-temperature stress is the most important limiting factor for its cultivation. To characterize the gene expression profiles of H. brasiliensis under the cold stress and discover the key cold stress-induced genes. Three cDNA libraries, CT (control), LT2 (cold treatment at 4 °C for 2 h) and LT24 (cold treatment at 4 °C for 24 h) were constructed for RNA sequencing (RNA-Seq) and gene expression profiling. Quantitative real time PCR (qRT-PCR) was conducted to validate the RNA-Seq and gene differentially expression results. A total of 1457 and 2328 differentially expressed genes (DEGs) in LT2 and LT24 compared with CT were respectively detected. Most significantly enriched KEGG pathways included flavonoid biosynthesis, phenylpropanoid biosynthesis, plant hormone signal transduction, cutin, suberine and wax biosynthesis, Pentose and glucuronate interconversions, phenylalanine metabolism and starch and sucrose metabolism. A total of 239 transcription factors (TFs) were differentially expressed following 2 h or/and 24 h of cold treatment. Cold-response transcription factor families included ARR-B, B3, BES1, bHLH, C2H, CO-like, Dof, ERF, FAR1, G2-like, GRAS, GRF, HD-ZIP, HSF, LBD, MIKC-MADS, M-type MADS, MYB, MYB-related, NAC, RAV, SRS, TALE, TCP, Trihelix, WOX, WRKY, YABBY and ZF-HD. The genome-wide transcriptional response of rubber tree to the cold treatments were determined and a large number of DEGs were characterized including 239 transcription factors, providing important clues for further elucidation of the mechanisms of cold stress responses in rubber tree.

YAP Is Essential for Treg-Mediated Suppression of Antitumor Immunity.

Regulatory T cells (Treg) are critical for maintaining self-tolerance and immune homeostasis, but their suppressive function can impede effective antitumor immune responses. FOXP3 is a transcription factor expressed in Tregs that is required for their function. However, the pathways and microenvironmental cues governing FOXP3 expression and Treg function are not completely understood. Herein, we report that YAP, a coactivator of the Hippo pathway, is highly expressed in Tregs and bolsters FOXP3 expression and Treg function in vitro and in vivo. This potentiation stemmed from YAP-dependent upregulation of activin signaling, which amplifies TGFß/SMAD activation in Tregs. YAP deficiency resulted in dysfunctional Tregs unable to suppress antitumor immunity or promote tumor growth in mice. Chemical YAP antagonism and knockout or blockade of the YAP-regulated activin receptor similarly improved antitumor immunity. Thus, we identify YAP as an unexpected amplifier of a Treg-reinforcing pathway with significant potential as an anticancer immunotherapeutic target.Significance: Tregs suppress antitumor immunity, and pathways supporting their function can be novel immunotherapy targets. Here, the selective expression of YAP by Tregs, its importance for their function, and its unexpected enhancement of pro-Treg Activin/SMAD signaling are reported, as are validations of potential cancer-fighting antagonists of YAP and its regulatory targets. Cancer Discov; 8(8); 1026-43. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 899.

Transcriptome analysis of Hevea brasiliensis in response to exogenous methyl jasmonate provides novel insights into regulation of jasmonate-elicited rubber biosynthesis.

The phytohomorne methyl jasmonate (MeJA) is known to trigger extensive reprogramming of gene expression leading to transcriptional activation of many secondary metabolic pathways. However, natural rubber is a commercially important secondary metabolite and little is known about the genetic and genomic basis of jasmonate-elicited rubber biosynthesis in rubber tree (Hevea brasiliensis). RNA sequencing (RNA-seq) of H. brasiliensis bark treated with 1 g lanolin paste containing 0.02% w/w MeJA for 24 h (M2) and 0.04% w/w MeJA for 24 h (M4) was performed. A total of 2950 and 2850 differentially expressed genes in M2 and M4 compared with control (C) were respectively detected. Key genes involved in 2-C-methyl-D-erythritol 4-phosphate, rubber biosynthesis, glycolysis and carbon fixation (Calvin cycle) pathway were found to be up-regulated by MeJA treatment. Particularly, the expression of 3-hydroxy-3-metylglutaryl coenzyme A reductase in MVA pathway was down-regulated by MeJA treatment, but the expression of farnesyl diphosphate synthase (FPS) and cis-prenyltransferase (CPT, or rubber transferase) in rubber biosynthesis pathway were up-regulated by MeJA treatment. Up-regulation of critical genes in JA biosynthesis in response to MeJA treatment exhibited the self-activation of JA biosynthesis. In addition, up-regulated genes of great regulatory importance in cross-talk between JA and other hormone signaling, and of transcriptional regulation were identified. The increased expression levels of FPS and CPT in rubber biosynthesis pathway possibly resulted in an increased latex production in rubber tree treated with MeJA. The present results provide insights into the mechanism by which MeJA activates the rubber biosynthesis and the transcriptome data can also serve as the foundation for future research into the molecular basis for MeJA regulation of other cellular processes.

Comprehensive integrative analyses identify GLT8D1 and CSNK2B as schizophrenia risk genes.

Recent genome-wide association studies (GWAS) have identified multiple risk loci that show strong associations with schizophrenia. However, pinpointing the potential causal genes at the reported loci remains a major challenge. Here we identify candidate causal genes for schizophrenia using an integrative genomic approach. Sherlock integrative analysis shows that ALMS1, GLT8D1, and CSNK2B are schizophrenia risk genes, which are validated using independent brain expression quantitative trait loci (eQTL) data and integrative analysis method (SMR). Consistently, gene expression analysis in schizophrenia cases and controls further supports the potential role of these three genes in the pathogenesis of schizophrenia. Finally, we show that GLT8D1 and CSNK2B knockdown promote the proliferation and inhibit the differentiation abilities of neural stem cells, and alter morphology and synaptic transmission of neurons. These convergent lines of evidence suggest that the ALMS1, CSNK2B, and GLT8D1 genes may be involved in pathophysiology of schizophrenia.

GRK5 functions as an oncogenic factor in non-small-cell lung cancer.

Lung cancer is the leading cause of cancer-related deaths worldwide, and non-small-cell lung cancer (NSCLC) accounts for about 80% of all cases, which is the major subgroup of lung cancer. G protein-coupled receptor kinase 5 (GRK5) has been demonstrated to play pivotal roles in both development and progression of several pathological conditions including cancer. Here, we found that GRK5 expression was significantly increased in 539 NSCLC cancerous tissues than that in 99 normal non-cancerous tissues by immunohistochemistry analysis; we also showed intensive higher positive staining percentage in female and adenocarcinoma (ADC) NSCLC patients than that in male and squamous cell carcinoma (SCC) patients, respectively. In addition, GRK5 high expression NSCLC patients had a worse overall survival rate than the low expression patients. We provided evidence showing that both the mRNA and protein expression levels of GRK5 were increased in NSCLC cancerous cell lines (GLC-82, SPC-A-1, H520, H838, H358, A549, and H1299) comparing with that in normal human bronchial epithelium cell line (BEAS-2B), and identified many GRK5 mutations in NSCLC cancerous tissues. In addition, we found that depletion of GRK5 inhibited NSCLC cancerous cell proliferation, migration in vitro, and xenograft tumor formation in vivo. Furthermore, GRK5 knockdown promoted cell cycle arrest at G2/M phase and induced cellular apoptosis. In summary, our data reveal an oncogenic role of GRK5 in NSCLC progression, indicating that GRK5 could be used as a new therapeutic target in future.

Establishment of basal cell carcinoma animal model in Chinese tree shrew (Tupaia belangeri chinensis).

Basal cell carcinoma (BCC) is the most common skin cancer worldwide, with incidence rates continuing to increase. Ultraviolet radiation is the major environmental risk factor and dysregulation of the Hedgehog (Hh) signaling pathway has been identified in most BCCs. The treatment of locally advanced and metastatic BBCs is still a challenge and requires a better animal model than the widely used rodents for drug development and testing. Chinese tree shrews (Tupaia belangeri chinensis) are closely related to primates, bearing many physiological and biochemical advantages over rodents for characterizing human diseases. Here, we successfully established a Chinese tree shrew BCC model by infecting tail skins with lentiviral SmoA1, an active form of Smoothened (Smo) used to constitutively activate the Hh signaling pathway. The pathological characteristics were verified by immunohistochemical analysis. Interestingly, BCC progress was greatly enhanced by the combined usage of lentiviral SmoA1 and shRNA targeting Chinese tree shrew p53. This work provides a useful animal model for further BCC studies and future drug discoveries.

A Normalization-Free and Nonparametric Method Sharpens Large-Scale Transcriptome Analysis and Reveals Common Gene Alteration Patterns in Cancers.

Heterogeneity in transcriptional data hampers the identification of differentially expressed genes (DEGs) and understanding of cancer, essentially because current methods rely on cross-sample normalization and/or distribution assumption-both sensitive to heterogeneous values. Here, we developed a new method, Cross-Value Association Analysis (CVAA), which overcomes the limitation and is more robust to heterogeneous data than the other methods. Applying CVAA to a more complex pan-cancer dataset containing 5,540 transcriptomes discovered numerous new DEGs and many previously rarely explored pathways/processes; some of them were validated, both in vitro and in vivo, to be crucial in tumorigenesis, e.g., alcohol metabolism (ADH1B), chromosome remodeling (NCAPH) and complement system (Adipsin). Together, we present a sharper tool to navigate large-scale expression data and gain new mechanistic insights into tumorigenesis.

NCAPH plays important roles in human colon cancer.

Colon cancer (CC) is one of the major malignancies worldwide, whose pathogenesis is complex and requires the accumulated alteration of multiple genes and signaling pathways. Condensins are multi-protein complexes that play pivotal roles in chromosome assembly and segregation during mitosis, meiosis and even tumorigenesis. Using tissue microarrays by immunohistochemistry and hematoxylin-eosin staining, we found that non-SMC condensin I complex subunit H (NCAPH) in colon cancerous tissues was higher than that in all corresponding adjacent non-cancerous tissues. We then characterized the exact function of the NCAPH in CC. We provided evidences showing that NCAPH is highly expressed in colorectal cancer cell lines comparing with normal human colonic epithelial cells, and identified many NCAPH mutations in CC patients. We found that depletion of NCAPH inhibits CC cell proliferation, migration in vitro and xenograft tumor formation in vivo. Furthermore, NCAPH knockdown promotes cell apoptosis and cell cycle arrest at G2/M phase. Interestingly, the NCAPH high expression in tumor tissues of colon patients had a significantly better prognosis and survival rate than low-expression patients, suggesting that NCAPH high expression promotes colonic cancerous cell proliferation; on the other hand, it may also sensitize these cells responding to chemo- or radio-therapies. Collectively, these findings reveal an important role of NCAPH in CC, indicating that NCAPH could be used as a new therapeutic target in future.

A comparison of toxicity and toxicokinetics in rats and dogs following twenty-eight-day, repeat-dose oral administration of nifurtimox.

Nifurtimox has been an important treatment for trypanosomiasis for many years, but new research indicates that the drug may also be an effective therapy for malignant neuroblastoma. However, there have been few published reports evaluating the toxicity of nifurtimox in different species. Therefore, to further understand its toxicity and toxicokinetic profiles, Sprague Dawley rats and beagle dogs were orally administered nifurtimox at 0, 25, 75 and 150 mg kg-1 day-1, and 0, 30, 60 and 120 mg kg-1 day-1, respectively, for 28 days, which was followed by a 28-day recovery period. Significant decreases in the body weight and food consumption were observed in rats given 75 and 150 mg kg-1 day-1, but no significant difference was observed in either body weight or food consumption in dogs. No notable gender difference was observed in the rats in our study. The mean Cmax and AUC0-t increased with the exposure time in rats, and systemic exposure on day 28 was notably higher than that on day 1 for each dosing group. In contrast, in dogs the mean Cmax and AUC0-t increased significantly in the 120 mg kg-1 day-1 group only. Other findings in rats included a dose-dependent increase in total bilirubin and urea, a significant increase in the kidney organ coefficient, a decrease in heart and thymus weights, and a decrease in the weight of testes and epididymides tissue in males administered 75 and 150 mg kg-1 day-1, with dead sperms observed in the epididymides and a loss of necrotic cells. Furthermore, the brains of rats administered 150 mg kg-1 day-1 nifurtimox revealed cerebral tissue softening. In dogs there were no treatment-related changes in organ weights during the dosing period. However, deciduous spermatoblasts were observed in the seminiferous tubules and there was a lack of long sperms in the epididymides. The findings from this study demonstrate inter-species differences in nifurtimox toxicity and toxicokinetics. These results are relevant to the evaluation of the wider clinical applications of this drug.

Genomic analysis of snub-nosed monkeys (Rhinopithecus) identifies genes and processes related to high-altitude adaptation.

The snub-nosed monkey genus Rhinopithecus includes five closely related species distributed across altitudinal gradients from 800 to 4,500 m. Rhinopithecus bieti, Rhinopithecus roxellana, and Rhinopithecus strykeri inhabit high-altitude habitats, whereas Rhinopithecus brelichi and Rhinopithecus avunculus inhabit lowland regions. We report the de novo whole-genome sequence of R. bieti and genomic sequences for the four other species. Eight shared substitutions were found in six genes related to lung function, DNA repair, and angiogenesis in the high-altitude snub-nosed monkeys. Functional assays showed that the high-altitude variant of CDT1 (Ala537Val) renders cells more resistant to UV irradiation, and the high-altitude variants of RNASE4 (Asn89Lys and Thr128Ile) confer enhanced ability to induce endothelial tube formation in vitro. Genomic scans in the R. bieti and R. roxellana populations identified signatures of selection between and within populations at genes involved in functions relevant to high-altitude adaptation. These results provide valuable insights into the adaptation to high altitude in the snub-nosed monkeys.

Apolipoprotein E Regulates Injury-Induced Activation of Hippocampal Neural Stem and Progenitor Cells.

Partial recovery from even severe traumatic brain injury (TBI) is ubiquitous and occurs largely through unknown mechanisms. Recent evidence suggests that hippocampal neural stem/progenitor cell (NSPC) activation and subsequent neurogenesis are responsible for at least some aspects of spontaneous recovery following TBI. Apolipoprotein E (ApoE) regulates postnatal neurogenesis in the hippocampus and is therefore a putative mediator of injury-induced neurogenesis. Further, ApoE isoforms in humans are associated with different cognitive outcomes following TBI. To investigate the role of ApoE in injury-induced neurogenesis, we exposed wild-type, ApoE-deficient, and human ApoE isoform-specific (ApoE3 and ApoE4) transgenic mice crossed with nestin-green fluorescent protein (GFP) reporter mice to controlled cortical impact (CCI) and assessed progenitor activation at 2 d post-injury using unbiased stereology. GFP+ progenitor cells were increased by approximately 120% in the ipsilateral hippocampus in injured wild-type mice, compared with sham mice (p<0.01). Co-localization of GFP+ cells with bromodeoxyrudine (BrdU) to label dividing cells indicated increased proliferation of progenitors in the injured hippocampus (p<0.001). This proliferative injury response was absent in ApoE-deficient mice, as no increase in GFP+ cells was observed in the injured hippocampus, compared with sham mice, despite an overall increase in proliferation indicated by increased BrdU+ cells (86%; p<0.05). CCI-induced proliferation of GFP+ cells in both ApoE3 and ApoE4 mice but the overall response was attenuated in ApoE4 mice due to fewer GFP+ cells at baseline. We demonstrate that ApoE is required for injury-induced proliferation of NSPCs after experimental TBI, and that this response is influenced by human APOE genotype.