Substance P in the medial amygdala regulates aggressive behaviors in male mice.

Behavioral and clinical studies have revealed a critical role of substance P (SP) in aggression; however, the neural circuit mechanisms underlying SP and aggression remain elusive. Here, we show that tachykinin-expressing neurons in the medial amygdala (MeATac1 neurons) are activated during aggressive behaviors in male mice. We identified MeATac1 neurons as a key mediator of aggression and found that MeATac1→ventrolateral part of the ventromedial hypothalamic nucleus (VMHvl) projections are critical to the regulation of aggression. Moreover, SP/neurokinin-1 receptor (NK-1R) signaling in the VMHvl modulates aggressive behaviors in male mice. SP/NK-1R signaling regulates aggression by influencing glutamate transmission in neurons in the VMHvl. In summary, these findings place SP as a key node in aggression circuits.

PRMT5-mediated homologous recombination repair is essential to maintain genomic integrity of neural progenitor cells.

Maintaining genomic stability is a prerequisite for proliferating NPCs to ensure genetic fidelity. Though histone arginine methylation has been shown to play important roles in safeguarding genomic stability, the underlying mechanism during brain development is not fully understood. Protein arginine N-methyltransferase 5 (PRMT5) is a type II protein arginine methyltransferase that plays a role in transcriptional regulation. Here, we identify PRMT5 as a key regulator of DNA repair in response to double-strand breaks (DSBs) during NPC proliferation. Prmt5F/F; Emx1-Cre (cKO-Emx1) mice show a distinctive microcephaly phenotype, with partial loss of the dorsal medial cerebral cortex and complete loss of the corpus callosum and hippocampus. This phenotype is resulted from DSBs accumulation in the medial dorsal cortex followed by cell apoptosis. Both RNA sequencing and in vitro DNA repair analyses reveal that PRMT5 is required for DNA homologous recombination (HR) repair. PRMT5 specifically catalyzes H3R2me2s in proliferating NPCs in the developing mouse brain to enhance HR-related gene expression during DNA repair. Finally, overexpression of BRCA1 significantly rescues DSBs accumulation and cell apoptosis in PRMT5-deficient NSCs. Taken together, our results show that PRMT5 maintains genomic stability by regulating histone arginine methylation in proliferating NPCs.

Schisandrin B Improves the Hypothermic Preservation of Celsior Solution in Human Umbilical Cord Mesenchymal Stem Cells.

BACKGROUND: Human umbilical cord mesenchymal stem cells (hUCMSCs) have emerged as promising therapy for immune and inflammatory diseases. However, how to maintain the activity and unique properties during cold storage and transportation is one of the key factors affecting the therapeutic efficiency of hUCMSCs. Schisandrin B (SchB) has many functions in cell protection as a natural medicine. In this study, we investigated the protective effects of SchB on the hypothermic preservation of hUCMSCs. METHODS: hUCMSCs were isolated from Wharton's jelly. Subsequently, hUCMSCs were exposed to cold storage (4 °C) and 24-h re-warming. After that, cells viability, surface markers, immunomodulatory effects, reactive oxygen species (ROS), mitochondrial integrity, apoptosis-related and antioxidant proteins expression level were evaluated. RESULTS: SchB significantly alleviated the cells injury and maintained unique properties such as differentiation potential, level of surface markers and immunomodulatory effects of hUCMSCs. The protective effects of SchB on hUCMSCs after hypothermic storage seemed associated with its inhibition of apoptosis and the anti-oxidative stress effect mediated by nuclear factor erythroid 2-related factor 2 signaling. CONCLUSION: These results demonstrate SchB could be used as an agent for hypothermic preservation of hUCMSCs.

A Nucleus Accumbens Tac1 Neural Circuit Regulates Avoidance Responses to Aversive Stimuli.

Neural circuits that control aversion are essential for motivational regulation and survival in animals. The nucleus accumbens (NAc) plays an important role in predicting aversive events and translating motivations into actions. However, the NAc circuits that mediate aversive behaviors remain elusive. Here, we report that tachykinin precursor 1 (Tac1) neurons in the NAc medial shell regulate avoidance responses to aversive stimuli. We show that NAcTac1 neurons project to the lateral hypothalamic area (LH) and that the NAcTac1→LH pathway contributes to avoidance responses. Moreover, the medial prefrontal cortex (mPFC) sends excitatory inputs to the NAc, and this circuit is involved in the regulation of avoidance responses to aversive stimuli. Overall, our study reveals a discrete NAc Tac1 circuit that senses aversive stimuli and drives avoidance behaviors.

Sodium Para-Aminosalicylic Acid Modulates Autophagy to Lessen Lead-Induced Neurodegeneration in Rat Cortex.

Lead (Pb) is a common heavy metal contaminant in the environment, and it may perturb autophagy and cause neurodegeneration. Although sodium para-aminosalicylic (PAS-Na) has been shown to protect the brain from lead-induced toxicity, the mechanisms associated with its efficacy have yet to be fully understood. In this study, we evaluated the efficacy of PAS-Na in attenuating the neurotoxic effects of lead, as well as the specific mechanisms that mediate such protection. Lead exposure resulted in weight loss and injury to the liver and kidney, and PAS-Na had a protective effect against this damage. Both short-term and subchronic lead exposure impaired learning ability, and this effect was reversed by PAS-Na intervention. Lead exposure also perturbed autophagic processes through the modulation of autophagy-related factors. Short-term lead exposure downregulated LC3 and beclin1 and upregulated the expression of p62; subchronic lead exposure upregulated the expression of LC3, beclin1, and P62. It follows that PAS-Na had an antagonistic effect on the activation of the above autophagy-related factors. Overall, our novel findings suggest that PAS-Na can protect the rat cortex from lead-induced toxicity by regulating autophagic processes. (1) Short-term lead exposure inhibits autophagy, whereas subchronic lead exposure promotes autophagy. (2) PAS-NA ameliorated the abnormal process of lead-induced autophagy, which had a protective effect on the cerebral cortex.

Dysregulation of AMPK-mTOR signaling leads to comorbid anxiety in Dip2a KO mice.

Autism is often comorbid with other psychiatric disorders. We have previously shown that Dip2a knockout (KO) induces autism-like behaviors in mice. However, the role of Dip2a in other psychiatric disorders remains unclear. In this paper, we revealed that Dip2a KO mice had comorbid anxiety. Dip2a KO led to a reduction in the dendritic length of cortical and hippocampal excitatory neurons. Molecular mechanism studies suggested that AMPK was overactivated and suppressed the mTOR cascade, contributing to defects in dendritic morphology. Deletion of Dip2a in adult-born hippocampal neurons (Dip2a conditional knockout (cKO)) increased susceptibility to anxiety upon acute stress exposure. Application of (2R,6R)-hydroxynorketamine (HNK), an inhibitor of mTOR, rescued anxiety-like behaviors in Dip2a KO and Dip2a cKO mice. In addition, 6 weeks of high-fat diet intake alleviated AMPK-mTOR signaling and attenuated the severity of anxiety in both Dip2a KO mice and Dip2a cKO mice. Taken together, these results reveal an unrecognized function of DIP2A in anxiety pathophysiology via regulation of AMPK-mTOR signaling.

Fine-scale genetic structure and wolbachia infection of aedes albopictus (Diptera: Culicidae) in Nanjing city, China.

Background: Aedes albopictus is an indigenous primary vector of dengue and Zika viruses in China. Wolbachia is a gram-negative and common intracellular bacteria, which is maternally inherited endosymbionts and could expand their propagation in host populations by means of various manipulations. Compared with research on the dispersion of Ae. albopictus at the macrospatial level (mainly at the country or continent level), little is known about its variation and Wolbachia infection at the microspatial level, which is essential for its management. Meanwhile, no local cases of dengue fever have been recorded in the history of Nanjing, which implies that few adulticides have been applied in the city. Thus, the present study examines how the Ae. albopictus population varies and the Wolbachia infection status of each population among microspatial regions of Nanjing City. Methods: The genetic structure of 17 Aedes albopictus populations collected from urban, urban fringe, and rural regions of Nanjing City was investigated based on 9 microsatellite loci and the mitochondrial coxI gene. The Wolbachia infection status of each population was also assessed with Wolbachia A- and Wolbachia B-specific primers. Results: Nine out of 58 tested pairs of microsatellite markers were highly polymorphic, with a mean PIC value of 0.560, and these markers were therefore chosen for microsatellite genotyping analysis. The Na value of each Ae. albopictus population was very high, and the urban area populations (7.353 ± 4.975) showed a lower mean value than the urban fringe region populations (7.866 ± 5.010). A total of 19 coxI haplotypes were observed among 329 Ae. albopictus individuals via haplotype genotyping, with the highest diversity observed among the urban fringe Ae. albopictus populations (Hd = 0.456) and the lowest among the urban populations (Hd = 0.277). Each Ae. albopictus population showed significant departure from HWE, and significant population expansion was observed in only three populations from the urban (ZSL), urban fringe (HAJY), and rural areas (HSZY) (p < 0.05). Combined with DAPC analysis, all the Ae. albopictus populations were adequately allocated to two clades with significant genetic differences according to population structure analysis, and the best K value was equal to two. AMOVA results showed that most (96.18%) of the genetic variation detected in Ae. albopictus occurred within individuals (FIT = 0.22238, p < 0.0001), while no significant positive correlation was observed via isolation by distance (IBD) analysis (R 2 = 0.03262, p = 0.584). The TCS network of all haplotypes showed that haplotype 1 (H1) and haplotype 4 (H4) were the most frequent haplotypes among all populations, and the haplotype frequency significantly increased from urban regions (36.84%) to rural regions (68.42%). Frequent migration was observed among Ae. albopictus populations from rural to urban regions via the urban fringe region, with four direct migration routes between rural and urban regions. Furthermore, Wolbachia genotyping results showed that most of the individuals of each population were coinfected with Wolbachia A and Wolbachia B. The independent infection rate of Wolbachia A was slightly higher than that of Wolbachia B, and no significant differences were observed among different regions. Conclusion: In the microspatial environment of Nanjing City, the urban fringe region is an important region for the dispersion of Ae. albopictus populations between rural and urban areas, and Wolbachia A and Wolbachia B coinfection is the most common Wolbachia infection status in all Ae. albopictus populations among different regions.

Establishment of a novel risk score for in-hospital mortality in adult sepsis patients.

Background: Existing scoring systems have limitations in predicting the in-hospital mortality of adult sepsis patients. We aimed to develop and validate a novel risk score for predicting the in-hospital mortality of adult sepsis patients. Methods: The clinical data of 1,335 adult sepsis inpatients were retrospectively analyzed. Enrolled patients were randomly divided into a modeling group and a validation group at a 3:2 ratio. The modeling group (n=801) was used to develop the risk score by univariate and multivariate logistic regression analyses. The score's performance was validated in the validation group (n=534). We classified patients into four risk levels according to the novel risk score. Results: Age, central vein catheterization, mechanical ventilation, vasopressin, Charlson comorbidity index (CCI), respiratory rate (RR), heart rate (HR), Glasgow coma scale (GCS) score, platelet (PLT), hematocrit (HCT), aspartate aminotransferase (AST), and activated partial thrombin time (APTT) were independent risk factors for in-hospital death in adult sepsis patients. Continuous variables were converted into classified variables to develop the risk score, with a total score of 39 points. Adult sepsis patients with low, lower medium, higher medium, and high risk levels had in-hospital mortality rates of 9.8%, 24.7%, 55.8%, and 83.5%, respectively. Conclusions: Compared with the Acute Physiology and Chronic Health Evaluation II scoring system (APACHE II) and the Modified Early Warning Score (MEWS), the novel risk score showed good predictive performance for in-hospital mortality in adult sepsis patients.

Critical Role of Neuronal Vps35 in Blood Vessel Branching and Maturation in Developing Mouse Brain.

Vps35 (vacuolar protein sorting 35), a key component of retromer, plays a crucial role in selective retrieval of transmembrane proteins from endosomes to trans-Golgi networks. Dysfunctional Vps35/retromer is a risk factor for the development of neurodegenerative diseases. Vps35 is highly expressed in developing pyramidal neurons, both in the mouse neocortex and hippocampus, Although embryonic neuronal Vps35's function in promoting neuronal terminal differentiation and survival is evident, it remains unclear whether and how neuronal Vps35 communicates with other types of brain cells, such as blood vessels (BVs), which are essential for supplying nutrients to neurons. Dysfunctional BVs contribute to the pathogenesis of various neurodegenerative disorders. Here, we provide evidence for embryonic neuronal Vps35 as critical for BV branching and maturation in the developing mouse brain. Selectively knocking out (KO) Vps35 in mouse embryonic, not postnatal, neurons results in reductions in BV branching and density, arteriole diameter, and BV-associated pericytes and microglia but an increase in BV-associated reactive astrocytes. Deletion of microglia by PLX3397 enhances these BV deficits in mutant mice. These results reveal the function of neuronal Vps35 in neurovascular coupling in the developing mouse brain and implicate BV-associated microglia as underlying this event.

Features and changes in retinal nerve fiber layer thickness in high myopic ocular hypertension: a 1-year prospective follow-up.

PURPOSE: To observe the features and changes in peripapillary retinal nerve fiber layer (pRNFL) thickness in highly myopic ocular hypertension (HM-OHT) patients. STUDY DESIGN: Prospective observation study. METHODS: Individuals who met the inclusion criteria were recruited into three groups: the healthy high myopia (HM), non-highly myopic ocular hypertension (OHT) and HM-OHT group. The spherical equivalent refraction, axial length, intraocular pressure, central corneal thickness and pRNFL thickness were collected and compared between groups. The OHT and HM-OHT group were followed up for 12 months. The changes in pRNFL thickness across the follow-up times were analyzed. RESULTS: The study included 92 subjects. The mean pRNFL thicknesses were 102.5 ± 11.1 µm in the HM (31 people), 101.9 ± 11.7 µm in the OHT (34 people) and 102.2 ± 12.0 µm in the HM-OHT group (27 people). There was no statistical difference in the mean pRNFL thickness among the three groups. The HM-HOT group and HM group had thicker temporal sectoral (p < 0.05) pRNFL thickness and thinner superior sectoral (p = 0.015) pRNFL thickness than the OHT group. During the 12-month follow-up, the mean pRNFL thickness of the HM OHT group decreased, with an annual reduction of -0.93 ± 0.14 µm. There was a significant difference across the three visits (p < 0.05), while there were no significant differences in the OHT group (p = 0.591). CONCLUSIONS: After ocular magnification correction, the HM-OHT group did not have thinner pRNFL thickness than the other two groups. However, the thickness decreased significantly over time.

[MRI-TRUS targeted biopsy combined with large-section prostate pathology for accurate diagnosis of prostate cancer].

Objective: To investigate the application value of MRI-transrectal ultrasound (TRUS) targeted biopsy combined with large-section prostate pathology in the diagnosis of prostate cancer (PCa). METHODS: Totally, 310 patients with suspected PCa underwent MRI-TRUS targeted biopsy combined with large-section prostate pathology (the observation group, n = 183) or standard 12-core TRUS biopsy (the control group, n = 127) in our hospital from January 2018 to December 2020. We compared the findings of biopsies and the detection rate of PCa between the two groups of patients. RESULTS: There were no statistically significant differences between the observation and control groups in the detection rates of PCa (35.52% vs 27.56%, P > 0.05), clinically significant PCa (30.60% vs 23.62%, P > 0.05) and clinically insignificant PCa (4.92% vs 3.94%, P > 0.05). The rate of positive punctures and the length of cancer tissue in the positive puncture were 27.50% and (4.68 ± 1.24) mm in the observation group, significantly higher than 22.38% and (3.70 ± 1.11) mm in the control (P < 0.05). The number of targeted punctures per case was markedly lower than that of system combined with targeted punctures (3 ï¼»1－5ï¼½ vs 15 ï¼»13－17ï¼½, P < 0.05). No statistically significant differences were observed between the targeted biopsy and system combined with targeted biopsy in the detection rates of PCa, clinically significant PCa and clinically insignificant PCa, the rate of positive punctures, or the length of cancer tissue in the positive puncture (P > 0.05). As the MRI features of PCa, the rates of T2WI low signal, irregular shape, blurred edge of lesions and DWI high signal were 63.08%, 76.92%, 83.08% and 84.62%, respectively, significantly higher than those of the benign lesions (P < 0.05), while the apparent diffusion coefficient (ADC) value of PCa was remarkably lower (ï¼»0.81 ± 0.15ï¼½ ×10－3mm2/s) than that of the benign lesions (P < 0.05). CONCLUSIONS: MRI-TRUS targeted biopsy combined with large-section prostate pathology has a high application value in the diagnosis of PCa, which can reduce the number of punctures and differentiate benign from malignant prostatic lesions in MRI images.

Roles of Nicotinamide N-Methyltransferase in Obesity and Type 2 Diabetes.

Type 2 diabetes (T2D) is thought to be a complication of metabolic syndrome caused by disorders of energy utilization and storage and characterized by insulin resistance or deficiency of insulin secretion. Though the mechanism linking obesity to the development of T2D is complex and unintelligible, it is known that abnormal lipid metabolism and adipose tissue accumulation possibly play important roles in this process. Recently, nicotinamide N-methyltransferase (NNMT) has been emerging as a new mechanism-of-action target in treating obesity and associated T2D. Evidence has shown that NNMT is associated with obesity and T2D. NNMT inhibition or NNMT knockdown significantly increases energy expenditure, reduces body weight and white adipose mass, improves insulin sensitivity, and normalizes glucose tolerance and fasting blood glucose levels. Additionally, trials of oligonucleotide therapeutics and experiments with some small-molecule NNMT inhibitors in vitro and in preclinical animal models have validated NNMT as a promising therapeutic target to prevent or treat obesity and associated T2D. However, the exact mechanisms underlying these phenomena are not yet fully understood and clinical trials targeting NNMT have not been reported until now. Therefore, more researches are necessary to reveal the acting mechanism of NNMT in obesity and T2D and to develop therapeutics targeting NNMT.

A Novel Netrin-1-Derived Peptide Enhances Protection against Neuronal Death and Mitigates of Intracerebral Hemorrhage in Mice.

It has been reported that Netrin-1 is involved in neuroprotection following injury to the central nervous system. However, the minimal functional domain of Netrin-1 which can preserve the neuroprotection but avoid the major side effects of Netrin remains elusive. Here, we investigated the neuroprotective effect of a peptide E1 derived from Netrin-1's EGF3 domain (residues 407-422). We found that it interacts with deleted colorectal carcinoma (DCC) to activate focal adhesion kinase phosphorylation exhibiting neuroprotection. The administration of the peptide E1 was able to improve functional recovery through reduced apoptosis in an experimental murine model of intracerebral hemorrhage (ICH). In summary, we reveal a functional sequence of Netrin-1 that is involved in the recovery process after ICH and identify a candidate peptide for the treatment of ICH.

DIP2A is involved in SOD-mediated antioxidative reactions in murine brain.

Autism spectrum disorders (ASDs) are highly associated with oxidative stress. We have recently shown that Disconnected-interacting protein homolog 2 A (DIP2A) functions in ASD pathophysiology by regulating cortactin acetylation for spine development and synaptic transmission. However, its role is not fully understood in the context of its abundant expression in mitochondria. In this paper, we found that DIP2A was involved in superoxide dismutase (SOD)-mediated antioxidative reactions. In mice, DIP2A knockout inhibited SOD activity and increased reactive oxygen species (ROS) levels in the cerebral cortex. In vitro gain-of-function experiments further confirmed the positive role of DIP2A in scavenging ROS upon oxidative stress. Moreover, DIP2A knockout caused irregular mitochondrial morphology in the cerebral cortex and impaired mitochondrial metabolism with an over consumption of lipids for energy supply. Taken together, these results revealed unrecognized functions of DIP2A in antioxidative protection, providing another possible explanation for DIP2A-mediated ASD pathophysiology.

Cortactin in Epithelial-Mesenchymal Transition.

Cortactin, a member of the actin-binding protein family, plays an important role in cell movement involving the cytoskeleton, as cell movement mediated by cortactin may induce the epithelial-mesenchymal transition. Cortactin participates in tumor proliferation, migration, and invasion and other related disease processes by binding to different proteins and participating in different pathways and mechanisms that induce the occurrence of these disease processes. Therefore, this article reviews the correlations between cortactin, the actin cytoskeleton, and the epithelial-mesenchymal transition and discusses its clinical importance in tumor therapy.

Nucleus Accumbens Tac1-Expressing Neurons Mediate Stress-Induced Anhedonia-like Behavior in Mice.

Major depressive disorder (MDD) presents with two primary symptoms: depressed mood and anhedonia, which suggests that distinct neuronal circuits may regulate MDD. However, the underlying circuits of these individual symptoms linked to depression remain elusive. Herein, we identify a discrete circuit of tachykinin precursor 1 (Tac1)-expressing neurons in the nucleus accumbens (NAc) lateral shell, which project to ventral pallidum and contribute to stress-induced anhedonia-like behavior. Selective inhibition and activation of Tac1NAc neurons bidirectionally modulate stress susceptibility, revealing that Tac1 neurons in the NAc are critical for regulating anhedonia-like behaviors. We find that a subpopulation of VP neurons receives inhibitory inputs from Tac1NAc neurons and exhibits decreased excitability in susceptible mice. Furthermore, the inhibition of the neurokinin 1 receptor promotes susceptibility to social stress. Overall, our study reveals a discrete circuit regulating anhedonia-like behavior in mice.

Myosin X Interaction with KIF13B, a Crucial Pathway for Netrin-1-Induced Axonal Development.

Myosin X (Myo X) transports cargos to the tips of filopodia for cell adhesion, migration, and neuronal axon guidance. Deleted in Colorectal Cancer (DCC) is one of the Myo X cargos that is essential for Netrin-1-regulated axon pathfinding. The function of Myo X in axon development in vivo and the underlying mechanisms remain elusive. Here, we provide evidence for the role of Myo X in Netrin-1-DCC-regulated axon development in developing mouse neocortex. The knockout (KO) or knockdown (KD) of Myo X in cortical neurons of embryonic mouse brain impairs axon initiation and contralateral branching/targeting. Similar axon deficits are detected in Netrin-1-KO or DCC-KD cortical neurons. Further proteomic analysis of Myo X binding proteins identifies KIF13B (a kinesin family motor protein). The Myo X interaction with KIF13B is induced by Netrin-1. Netrin-1 promotes anterograde transportation of Myo X into axons in a KIF13B-dependent manner. KIF13B-KD cortical neurons exhibit similar axon deficits. Together, these results reveal Myo X-KIF13B as a critical pathway for Netrin-1-promoted axon initiation and branching/targeting.SIGNIFICANCE STATEMENT Netrin-1 increases Myosin X (Myo X) interaction with KIF13B, and thus promotes axonal delivery of Myo X and axon initiation and contralateral branching in developing cerebral neurons, revealing unrecognized functions and mechanisms underlying Netrin-1 regulation of axon development.

Ependymal Vps35 Promotes Ependymal Cell Differentiation and Survival, Suppresses Microglial Activation, and Prevents Neonatal Hydrocephalus.

Hydrocephalus is a pathologic condition associated with various brain diseases, including Alzheimer's disease (AD). Dysfunctional ependymal cells (EpCs) are believed to contribute to the development of hydrocephalus. It is thus of interest to investigate EpCs' development and function. Here, we report that vacuolar protein sorting-associated protein 35 (VPS35) is critical for EpC differentiation, ciliogenesis, and survival, and thus preventing neonatal hydrocephalus. VPS35 is abundantly expressed in EpCs. Mice with conditional knock-out (cKO) of Vps35 in embryonic (Vps35GFAP-Cre and Vps35Emx1-Cre) or postnatal (Vps35Foxj1-CreER) EpC progenitors exhibit enlarged lateral ventricles (LVs) and hydrocephalus-like pathology. Further studies reveal marked reductions in EpCs and their cilia in both Vps35GFAP-Cre and Vps35Foxj1-CreER mutant mice. The reduced EpCs appear to be due to impairments in EpC differentiation and survival. Additionally, both Vps35GFAP-Cre and Vps35Foxj1-CreER neonatal pups exhibit increased cell proliferation and death largely in a region close to LV-EpCs. Many microglia close to the mutant LV-EpC region become activated. Depletion of the microglia by PLX3397, an antagonist of colony-stimulating factor 1 receptor (CSF1R), restores LV-EpCs and diminishes the pathology of neonatal hydrocephalus in Vps35Foxj1-CreER mice. Taken together, these observations suggest unrecognized functions of Vps35 in EpC differentiation, ciliogenesis, and survival in neonatal LV, and reveal pathologic roles of locally activated microglia in EpC homeostasis and hydrocephalus development.SIGNIFICANCE STATEMENT This study reports critical functions of vacuolar protein sorting-associated protein 35 (VPS35) not only in promoting ependymal cell (EpC) differentiation, ciliogenesis, and survival, but also in preventing local microglial activation. The dysfunctional EpCs and activated microglia are likely to induce hydrocephalus.

DIP2B Interacts With α-Tubulin to Regulate Axon Outgrowth.

Axonal development is essential to the establishment of neuronal morphology and circuitry, although the mechanisms underlying axonal outgrowth during the early developmental stages remain unclear. Here, we showed that the conserved disco-interacting protein B (DIP2B) which consists of a DMAP1 domain and a crotonobetaine/carnitine CoA ligase (Caic) domain, is highly expressed in the excitatory neurons of the hippocampus. DIP2B knockout led to excessive axonal outgrowth but not polarity at an early developmental stage. Furthermore, the loss of DIP2B inhibited synaptic transmission for both spontaneous and rapid release in cultured hippocampal neurons. Interestingly, DIP2B function during axonal outgrowth requires tubulin acetylation. These findings reveal a new conserved regulator of neuronal morphology and provide a novel intervention mechanism for neurocognitive disorders.

Human antigen R-regulated mRNA metabolism promotes the cell motility of migrating mouse neurons.

Neocortex development during embryonic stages requires the precise control of mRNA metabolism. Human antigen R (HuR) is a well-studied mRNA-binding protein that regulates mRNA metabolism, and it is highly expressed in the neocortex during developmental stages. Deletion of HuR does not impair neural progenitor cell proliferation or differentiation, but it disturbs the laminar structure of the neocortex. We report that HuR is expressed in postmitotic projection neurons during mouse brain development. Specifically, depletion of HuR in these neurons led to a mislocalization of CDP+ neurons in deeper layers of the cortex. Time-lapse microscopy showed that HuR was required for the promotion of cell motility in migrating neurons. PCR array identified profilin 1 (Pfn1) mRNA as a major binding partner of HuR in neurons. HuR positively mediated the stability of Pfn1 mRNA and influenced actin polymerization. Overexpression of Pfn1 successfully rescued the migration defects of HuR-deleted neurons. Our data reveal a post-transcriptional mechanism that maintains actin dynamics during neuronal migration.