Role In Neuronal Development Research Articles

Abstract 3117: Pleiotrophin is a marker of poor prognosis in Middle Eastern papillary thyroid carcinoma

Abstract Pleiotrophin (PTN) is a heparin binding growth factor known to have role in neuronal development. It is highly expressed in embryo but has a very limited expression in adult tissues. PTN is considered a proto-oncogene and has been hypothesized to play role in oncogenesis as its expression is found to be increased in many different cancer subtypes. Its role in cell transformation, cell growth, survival, migration and angiogenesis has also been shown in various different types of cancers. The function of PTN is hypothesized to be carried out by its interaction with cell surface proteoglycans or binding to its selective cell surface receptor, protein tyrosine phosphatase receptor Z1 (PTPRZ1). The significance of role of PTN in pathogenesis of thyroid cancer has not been explored especially with the fact that papillary thyroid carcinoma (PTC) originating in this ethnic population is the second most common female malignancy, after breast. So in search for novel druggable molecular target we sought for PTN expression in a large cohort of Saudi PTC. We analysed PTN alteration in more than 1000 primary papillary thyroid carcinoma in a tissue microarray format with clinical follow up data. We found that PTN was overexpressed in 65.5% (658/1006) of PTC and was significantly associated with aggressive clinical parameters such as tall cell variant histological subtype (p = 0.0333), extrathyroidal extension (p = 0.0292), lymphovascular invasion (p = 0.0182) and large tumour size (p = 0.0160). Important significant molecular association was seen with PTPRZ-1 (p = 0.0316), Midkine (p = 0.0008) and pSTAT-3 (p<0.0001). Finally patients showing PTN overexpression have worse disease free survival compared to patients showing low or absent PTN expression (p = 0.0218). On multivariate analysis PTN is found to be an independent marker of poor prognosis taking into consideration parameters such as Age, Stage, Lymph node status and Extrathyroidal extension (p = 0.0430). This study highlights the importance of PTN as druggable molecular target which can be therapeutically exploited by its inhibitors in treatment of PTC. Keywords: Papillary Thyroid Cancer; Pleiotrophin; Pleiotrophin Receptor Citation Format: Shaham Beg, Maqbool Ahmed, Azhar Hussein, Rong Bu, Zeeshan Qadri, Saif AlSobhi, Fouad Al Dayel, Abdul K. Siraj, Khawla S. Al-Kuraya. Pleiotrophin is a marker of poor prognosis in Middle Eastern papillary thyroid carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3117.

Identification of consensus binding sites clarifies FMRP binding determinants

Fragile X mental retardation protein (FMRP) is a multifunctional RNA-binding protein with crucial roles in neuronal development and function. Efforts aimed at elucidating how FMRP target mRNAs are selected have produced divergent sets of target mRNA and putative FMRP-bound motifs, and a clear understanding of FMRP's binding determinants has been lacking. To clarify FMRP's binding to its target mRNAs, we produced a shared dataset of FMRP consensus binding sequences (FCBS), which were reproducibly identified in two published FMRP CLIP sequencing datasets. This comparative dataset revealed that of the various sequence and structural motifs that have been proposed to specify FMRP binding, the short sequence motifs TGGA and GAC were corroborated, and a novel TAY motif was identified. In addition, the distribution of the FCBS set demonstrates that FMRP preferentially binds to the coding region of its targets but also revealed binding along 3′ UTRs in a subset of target mRNAs. Beyond probing these putative motifs, the FCBS dataset of reproducibly identified FMRP binding sites is a valuable tool for investigating FMRP targets and function.

Effects of maternal vitamin B12 supplementation on early infant neurocognitive outcomes: a randomized controlled clinical trial.

Maternal nutritional status during pregnancy impacts fetal brain development. Vitamin B12 plays a vital role in neuronal development. However, findings from studies on the association between maternal B12 status and child cognitive functions have been inconsistent. We performed a randomized, placebo-controlled clinical trial of oral B12 supplementation (50 µg) beginning at <14 weeks of gestation through a 6-week post-partum. In the present study, we report the effects of maternal B12 supplementation on cognitive development in infants at 9 months of age on Bayley Scales of Infant Development-III (BSID-III). One hundred eighty-three pregnant women received vitamin B12, and 183 received placebo. Nine-month BSID-III development score was available in 178 infants. There were no significant differences in maternal sociodemographic characteristics and baseline biochemical measures between infants who underwent BSID-III evaluation and infants who were not evaluated. There were no significant differences in any of the subscales of BSID-III between infants born to mothers who received B12 supplementation (n = 78) vs. placebo (n = 100). On multiple regression analysis, elevated maternal total homocysteine (tHcy) levels adjusted for treatment group, birthweight, parity, income and home environment at second trimester of pregnancy were significantly negatively associated with expressive language (β = 3.13 points, P < 0.001), and in third trimester of pregnancy with expressive language (β = -2.29 points, P < 0.001) and fine motor (β = -1.41 points, P = 0.005) domains of BSID-III. While no significant effects of maternal B12 supplementation were seen on cognitive development in infants at 9 months of age, elevated maternal tHcy levels were associated with poorer cognitive performance in some of the subdomains of BSID-III. In pregnant women with elevated tHcy levels and or B12 deficiencies, it may be worthwhile to study the impact of longer term maternal supplementation on infant cognitive outcomes.

Loss of Transient Receptor Potential Ankyrin 1 Channel Deregulates Emotion, Learning and Memory, Cognition, and Social Behavior in Mice.

The transient receptor potential ankyrin 1 (TRPA1) channel is a non-selective cation channel that helps regulate inflammatory pain sensation and nociception and the development of inflammatory diseases. However, the potential role of the TRPA1 channel and the underlying mechanism in brain functions are not fully resolved. In this study, we demonstrated that genetic deletion of the TRPA1 channel in mice or pharmacological inhibition of its activity increased neurite outgrowth. In vivo study in mice provided evidence of the TRPA1 channel as a negative regulator in hippocampal functions; functional ablation of the TRPA1 channel in mice enhanced hippocampal functions, as evidenced by less anxiety-like behavior, and enhanced fear-related or spatial learning and memory, and novel location recognition as well as social interactions. However, the TRPA1 channel appears to be a prerequisite for motor function; functional loss of the TRPA1 channel in mice led to axonal bundle fragmentation, downregulation of myelin basic protein, and decreased mature oligodendrocyte population in the brain, for impaired motor function. The TRPA1 channel may play a crucial role in neuronal development and oligodendrocyte maturation and be a potential regulator in emotion, cognition, learning and memory, and social behavior.

Investigating the effects of copy number variants on reading and language performance.

BackgroundReading and language skills have overlapping genetic bases, most of which are still unknown. Part of the missing heritability may be caused by copy number variants (CNVs).MethodsIn a dataset of children recruited for a history of reading disability (RD, also known as dyslexia) or attention deficit hyperactivity disorder (ADHD) and their siblings, we investigated the effects of CNVs on reading and language performance. First, we called CNVs with PennCNV using signal intensity data from Illumina OmniExpress arrays (~723,000 probes). Then, we computed the correlation between measures of CNV genomic burden and the first principal component (PC) score derived from several continuous reading and language traits, both before and after adjustment for performance IQ. Finally, we screened the genome, probe-by-probe, for association with the PC scores, through two complementary analyses: we tested a binary CNV state assigned for the location of each probe (i.e., CNV+ or CNV−), and we analyzed continuous probe intensity data using FamCNV.ResultsNo significant correlation was found between measures of CNV burden and PC scores, and no genome-wide significant associations were detected in probe-by-probe screening. Nominally significant associations were detected (p~10−2–10−3) within CNTN4 (contactin 4) and CTNNA3 (catenin alpha 3). These genes encode cell adhesion molecules with a likely role in neuronal development, and they have been previously implicated in autism and other neurodevelopmental disorders. A further, targeted assessment of candidate CNV regions revealed associations with the PC score (p~0.026–0.045) within CHRNA7 (cholinergic nicotinic receptor alpha 7), which encodes a ligand-gated ion channel and has also been implicated in neurodevelopmental conditions and language impairment. FamCNV analysis detected a region of association (p~10−2–10−4) within a frequent deletion ~6 kb downstream of ZNF737 (zinc finger protein 737, uncharacterized protein), which was also observed in the association analysis using CNV calls.ConclusionsThese data suggest that CNVs do not underlie a substantial proportion of variance in reading and language skills. Analysis of additional, larger datasets is warranted to further assess the potential effects that we found and to increase the power to detect CNV effects on reading and language.Electronic supplementary materialThe online version of this article (doi:10.1186/s11689-016-9147-8) contains supplementary material, which is available to authorized users.

Association study of MiRSNPs with schizophrenia, tardive dyskinesia and cognition

MicroRNAs (miRNAs) bind to 3′UTRs of genes and negatively regulate their expression. With ~50% of miRNAs expressing in the brain, they play an important role in neuronal development, plasticity, cognition and neurological disorders. Conserved miRNA targets are present in >60% genes in humans and are under evolutionary pressure to maintain pairing with miRNA. However, such binding may be affected by genetic variant(s) in the target sites (MiRSNPs), thereby altering gene expression. Differential expression of a large number of genes in postmortem brains of schizophrenia (SZ) patients compared to controls has been documented. Thus studying the role of MiRSNPs which are underinvestigated in SZ becomes attractive. We systematically selected 35 MiRSNPs with predicted functional relevance in 3′UTRs of genes shown previously to be associated with SZ, genotyped and tested their association with disease, using independent discovery and replication samples (total n=1017 cases; n=1073 controls). We also explored genetic associations with two sets of quantitative traits, namely tardive dyskinesia (TD) and cognitive functions disrupted in SZ in subsets of the study cohort. In the primary analysis, a significant association of MiRSNP rs7430 at PPP3CC was observed with SZ in the discovery and the replication samples [discovery: P=0.01; OR (95% CI) 1.24 (1.04–1.48); replication: P=0.03; OR (95% CI) 1.20 (1.02–1.43)]. In the exploratory analyses, five SNPs were nominally associated with TD (P values 0.04–0.004). Separately, 12 SNPs were associated with one or more of the eight cognitive domains (P values 0.05–0.003). These associations, particularly the SNP at PPP3CC merit further investigations.

Dissecting the role of redox signaling in neuronal development.

The generation of abnormally high levels of reactive oxygen species (ROS) is linked to cellular dysfunction, including neuronal toxicity and neurodegeneration. However, physiological ROS production modulates redox-sensitive roles of several molecules such as transcription factors, signaling proteins, and cytoskeletal components. Changes in the functions of redox-sensitive proteins may be important for defining key aspects of stem cell proliferation and differentiation, neuronal maturation, and neuronal plasticity. In neurons, most of the studies have been focused on the pathological implications of such modifications and only very recently their essential roles in neuronal development and plasticity has been recognized. In this review, we discuss the participation of NADPH oxidases (NOXs) and a family of protein-methionine sulfoxide oxidases, named molecule interacting with CasLs, as regulated enzymatic sources of ROS production in neurons, and describes the contribution of ROS signaling to neurogenesis and differentiation, neurite outgrowth, and neuronal plasticity. We review the role of reactive oxygen species (ROS) in neurogenesis, axon growth, and guidance and NMDA-receptor-mediated plasticity, LTP, and memory. ROS participation is presented in the context of NADPH oxidase and MICAL functions and their importance for brain functions.

DISC1-dependent Regulation of Mitochondrial Dynamics Controls the Morphogenesis of Complex Neuronal Dendrites

The DISC1 protein is implicated in major mental illnesses including schizophrenia, depression, bipolar disorder, and autism. Aberrant mitochondrial dynamics are also associated with major mental illness. DISC1 plays a role in mitochondrial transport in neuronal axons, but its effects in dendrites have yet to be studied. Further, the mechanisms of this regulation and its role in neuronal development and brain function are poorly understood. Here we have demonstrated that DISC1 couples to the mitochondrial transport and fusion machinery via interaction with the outer mitochondrial membrane GTPase proteins Miro1 and Miro2, the TRAK1 and TRAK2 mitochondrial trafficking adaptors, and the mitochondrial fusion proteins (mitofusins). Using live cell imaging, we show that disruption of the DISC1-Miro-TRAK complex inhibits mitochondrial transport in neurons. We also show that the fusion protein generated from the originally described DISC1 translocation (DISC1-Boymaw) localizes to the mitochondria, where it similarly disrupts mitochondrial dynamics. We also show by super resolution microscopy that DISC1 is localized to endoplasmic reticulum contact sites and that the DISC1-Boymaw fusion protein decreases the endoplasmic reticulum-mitochondria contact area. Moreover, disruption of mitochondrial dynamics by targeting the DISC1-Miro-TRAK complex or upon expression of the DISC1-Boymaw fusion protein impairs the correct development of neuronal dendrites. Thus, DISC1 acts as an important regulator of mitochondrial dynamics in both axons and dendrites to mediate the transport, fusion, and cross-talk of these organelles, and pathological DISC1 isoforms disrupt this critical function leading to abnormal neuronal development.

Regenerating white matter using human iPSC-derived immature astroglia

Astrocytes traditionally were thought to have merely a support function, but are now understood to be important regulators of neural development and function. The immature and mature astrocytes have stage-specific roles in neuronal development. However, it is largely unclear whether human astrocytes also serve stage-specific roles in oligodendroglial development. Owing to the broad and diverse roles of astroglia in the central nervous system, transplantation of astroglia also could be of therapeutic value in promoting regeneration after CNS injury or disease. Our recent study (Jiang etal., 2016) explores the developmental interactions between astroglia and oligodendroglia, using a human induced pluripotent stem cell (hiPSC) model. By generating immature and mature human astrocytes from hiPSCs, we reveal previously unrecognized effects of immature human astrocytes on oligodendrocyte development. Notably, tissue inhibitor of metalloproteinase-1 (TIMP-1) is differentially expressed in the immature and mature human astrocytes, and mediates at least in part the effects of immature human astrocytes on oligodendroglial differentiation. Furthermore, we demonstrate that hiPSC-derived astroglial transplants promote cerebral white matter regeneration and behavioral recovery in a neonatal mouse model of hypoxic-ischemic injury. Our study provides novel insights into the astro-oligodendroglial cell interaction and has important implications for possible therapeutic interventions for human white matter diseases.

Neurotrophin, p75, and Trk Signaling Module in the Developing Nervous System of the Marine Annelid Platynereis dumerilii.

In vertebrates, neurotrophic signaling plays an important role in neuronal development, neural circuit formation, and neuronal plasticity, but its evolutionary origin remains obscure. We found and validated nucleotide sequences encoding putative neurotrophic ligands (neurotrophin, NT) and receptors (Trk and p75) in two annelids, Platynereis dumerilii (Errantia) and Capitella teleta (Sedentaria, for which some sequences were found recently by Wilson, 2009). Predicted protein sequences and structures of Platynereis neurotrophic molecules reveal a high degree of conservation with the vertebrate counterparts; some amino acids signatures present in the annelid Trk sequences are absent in the basal chordate amphioxus, reflecting secondary loss in the cephalochordate lineage. In addition, expression analysis of NT, Trk, and p75 during Platynereis development by whole-mount mRNA in situ hybridization supports a role of these molecules in nervous system and circuit development. These annelid data corroborate the hypothesis that the neurotrophic signaling and its involvement in shaping neural networks predate the protostome-deuterostome split and were present in bilaterian ancestors.

The Role of Purα in Neuronal Development, the Progress in the Current Researches

As a ubiquitous protein in the body, Purα has been considered to possess multiple regulatory functions from DNA replication and transcription to RNA transport and translation. The recent studies have proved that Purα protein played a vital role in neuronal development with the solid and abundant evidence both in transgenic mice and human genetic DNA analysis. The Pur knocked out mice models have been successfully established in two independent research groups and their results demonstrated that lack of Purα alters postnatal brain development. Mice lacking of Purα display decreased neurogenesis and impaired neuronal development. In the mouse brain, the expression level of Purα seems to be regulated with brain development. It starts to express Purα after birth and quickly reach to highest level in the third week. The recent studies also have proved that some neurodegenerative disease also linked with Purα, such as fragile X-associated tremor/ataxia syndrome. rCGG-mediated neuronal toxicity could be modulated by heterogeneous nuclear ribonucleoprotein A2/B1 and Purα, which is rCGG-repeat-binding proteins. The 5q31.3 Microdeletion Syndrome is another disorder that is associated with the mutation of Purα gene, it has been demonstrated that all the symptoms such as the neurocognitive impairment, neurodevelopmental delay and learning disability are caused by the mutation of Purα gene. In this mini review, we will retrospectively review the current progress of Purα in neuronal development and try to figure out the connections between these observed phenomena and the biological function of Purα.

Novel Therapeutic Approach for Autism Spectrum Disorder: Focus on SHANK3.

SHANK3 is a synaptic scaffolding protein and plays an important role in neuronal development. SHANK3 interacts with various synaptic molecules, including post-synaptic density-95 (PSD-95), homer and GluR1 AMPA receptor. SHANK3 gene is a causable gene of the Phelan- McDermid syndrome (also known as the 22q13.3 deletion syndrome), whose manifestation is global developmental delay and autistic behavior, especially shows severe speech and language deficit. Additionally since cumulative gene analysis in autistic subjects identified several mutations in SHANK3 gene, including deletion and duplication in a particular region, abnormality of SHANK3 gene is thought the be related with the neuropathology of autism spectrum disorder (ASD). We here review the recent findings in regard to the roles of SHANK3 in higher brain functions, molecular-biologic studies of the complex expression of Shank3 transcripts and production of SHANK3 isoforms, and behavioral studies of Shank3-mutant mice, including our recent findings, and discuss a novel therapeutic approach for ASD.

Cognitive Impairment in Schizophrenia: Interplay of BDNF and Childhood Trauma? A Review of Literature.

Cognitive impairment is a core feature of schizophrenia. These deficits can also serve as an endophenotype for the illness in genetic studies. There is evidence that suggests that cognition can be considered a reasonable target for intervention in both schizophrenia and bipolar disorder. One of the most studied genetic phenotypes for psychosis is brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms. BDNF has an established role in neuronal development and cell survival in response to stress and is abnormally expressed in schizophrenia. Studies have shown that childhood trauma is associated with poor prognosis of schizophrenic patients. BDNF-Val66Met polymorphism has been shown to moderate the impact of childhood adversity on later expression of affective symptoms, suggesting the possibility of gene environment interactions. Considering the recent advances of neuroscience an up to date review of relevant literature is warranted in this field. This article reviews the current literature available regarding associations between the Val66Met polymorphism, childhood trauma and cognitive dysfunction in schizophrenia.

PLD1 participates in BDNF-induced signalling in cortical neurons.

The brain-derived neurotrophic factor BDNF plays a critical role in neuronal development and the induction of L-LTP at glutamatergic synapses in several brain regions. However, the cellular and molecular mechanisms underlying these BDNF effects have not been firmly established. Using in vitro cultures of cortical neurons from knockout mice for Pld1 and Rsk2, BDNF was observed to induce a rapid RSK2-dependent activation of PLD and to stimulate BDNF ERK1/2-CREB and mTor-S6K signalling pathways, but these effects were greatly reduced in Pld1−/− neurons. Furthermore, phospho-CREB did not accumulate in the nucleus, whereas overexpression of PLD1 amplified the BDNF-dependent nuclear recruitment of phospho-ERK1/2 and phospho-CREB. This BDNF retrograde signalling was prevented in cells silenced for the scaffolding protein PEA15, a protein which complexes with PLD1, ERK1/2, and RSK2 after BDNF treatment. Finally PLD1, ERK1/2, and RSK2 partially colocalized on endosomal structures, suggesting that these proteins are part of the molecular module responsible for BDNF signalling in cortical neurons.

Phosphorylation by PKA and Cdk5 Mediates the Early Effects of Synapsin III in Neuronal Morphological Maturation.

Synapsin III (SynIII) is a neuron-specific phosphoprotein that plays a unique role in neuronal development. SynIII is phosphorylated by cAMP-dependent protein kinase (PKA) at a highly conserved phosphorylation site and by cyclin-dependent kinase-5 (Cdk5) at a newly described site. Although SynIII is known to be involved in axon elongation in vitro, the role of its phosphorylation by PKA and Cdk5 in the modulation of this process is unknown. We expressed either wild-type (WT) or phosphorylation-site mutants of SynIII in primary SynIII knock-out (KO) mouse neurons at early stages of in vitro development. Whereas the neurite elongation phenotype of SynIII KO neurons was fully rescued by the expression of WT SynIII, the expression of nonphosphorylatable and pseudo-phosphorylated PKA mutants was ineffective. Also, the nonphosphorylatable Cdk5 mutant was unable to rescue the neurite elongation phenotype of SynIII KO neurons. By contrast, the pseudo-phosphorylated mutant rescued the delay in neuronal maturation and axonal elongation, revealing a Cdk5-dependent regulation of SynIII function. Interestingly, SynIII KO neurons also exhibited decreased survival that was fully rescued by the expression of WT SynIII, but not by its phosphorylation mutants, and was associated with increased activated caspase3 and altered tropomyosin receptor kinase B isoform expression. These results indicate that PKA and Cdk5 phosphorylation is required for the physiological action of SynIII on axon specification and neurite outgrowth and that the expression of a functional SynIII is crucial for cell survival. Significance statement: Synapsin III is an atypical member of the synapsin family of synaptic vesicle-associated phosphoproteins that is precociously expressed in neurons and is downregulated afterward. Although experimental evidence suggests a specific role for Synapsin III in neuronal development, the molecular mechanisms are still largely unknown. We found that Synapsin III plays a central role in early stages of neuronal development involving neuronal survival, polarization, and neuritic growth and that these effects are dependent on phosphorylation by cAMP-dependent protein kinase and cyclin-dependent protein kinase-5. These results explain the recently described neurodevelopmental defects in the migration and orientation of Synapsin III-depleted cortical neurons and support the potential association of Synapsin III with neurodevelopmental disorders such as schizophrenia.

Quantifying mechanical force in axonal growth and guidance.

Mechanical force plays a fundamental role in neuronal development, physiology, and regeneration. In particular, research has shown that force is involved in growth cone-mediated axonal growth and guidance as well as stretch-induced elongation when an organism increases in size after forming initial synaptic connections. However, much of the details about the exact role of force in these fundamental processes remain unknown. In this review, we highlight: (1) standing questions concerning the role of mechanical force in axonal growth and guidance; and (2) different experimental techniques used to quantify forces in axons and growth cones. We believe that satisfying answers to these questions will require quantitative information about the relationship between elongation, forces, cytoskeletal dynamics, axonal transport, signaling, substrate adhesion, and stiffness contributing to directional growth advance. Furthermore, we address why a wide range of force values have been reported in the literature, and what these values mean in the context of neuronal mechanics. We hope that this review will provide a guide for those interested in studying the role of force in development and regeneration of neuronal networks.

Concentration and Localization of Coexpressed ELAV/Hu Proteins Control Specificity of mRNA Processing.

Neuronally coexpressed ELAV/Hu proteins comprise a family of highly related RNA binding proteins which bind to very similar cognate sequences. How this redundancy is linked to in vivo function and how gene-specific regulation is achieved have not been clear. Analysis of mutants in Drosophila ELAV/Hu family proteins ELAV, FNE, and RBP9 and of genetic interactions among them indicates that they have mostly independent roles in neuronal development and function but have converging roles in the regulation of synaptic plasticity. Conversely, ELAV, FNE, RBP9, and human HuR bind ELAV target RNA in vitro with similar affinities. Likewise, all can regulate alternative splicing of ELAV target genes in nonneuronal wing disc cells and substitute for ELAV in eye development upon artificially increased expression; they can also substantially restore ELAV's biological functions when expressed under the control of the elav gene. Furthermore, ELAV-related Sex-lethal can regulate ELAV targets, and ELAV/Hu proteins can interfere with sexual differentiation. An ancient relationship to Sex-lethal is revealed by gonadal expression of RBP9, providing a maternal fail-safe for dosage compensation. Our results indicate that highly related ELAV/Hu RNA binding proteins select targets for mRNA processing through alteration of their expression levels and subcellular localization but only minimally by altered RNA binding specificity.

Population difference in the association of BDNF promoter methylation with mild cognitive impairment in the Xinjiang Uygur and Han populations

BackgroundMild cognitive impairment (MCI) is a clinical transitional stage between normal aging and Alzheimer disease, which leads to memory loss and a reduction in cognitive function. Brain derived neurotrophic factor (BDNF) plays an important role in neuronal development and plasticity. The aim of this study was to explore the association between BDNF promoter methylation and MCI in the Xinjiang Uygur and Han populations. MethodsA DNA methylation assay using bisulfite pyrosequencing technology was performed on 96 Uygur and 96 Han Chinese individuals from Xinjiang province, China. ResultsWe found a significantly higher BDNF methylation level in Han MCI cases than in Uygur MCI cases in males from Xinjiang province (p=0.022). In addition, the methylation level was significantly higher in Xinjiang Han healthy Chinese individuals (Northwestern China) than in Ningbo Han healthy Chinese individuals (Southeastern China) (Female and Male: p=1.17E−05; Female: p=0.020; Male: p=1.37E−04). But our results showed no significant association of BDNF methylation with MCI in either the Uygur or Han Chinese populations (p>0.05). Further gender-based subgroup analyses did not find any significant results (p>0.05). ConclusionOur results indicate that different levels of BDNF methylation may be present in different populations and environments. This study also provides further information regarding the relationship between BDNF methylation levels and MCI in Xinjiang Uygur and Han ethnic groups.

Prolonged hyperglycemia & hyperinsulinemia increases BDNF mRNA expression in the posterior ventromedial hypothalamus and the dorsomedial hypothalamus of fed female rats.

Brain-derived neurotrophic factor (BDNF) plays a key role in neuronal development, synaptic plasticity, and the central control of energy homeostasis. Peripheral metabolic signals such as leptin and glucose regulate hypothalamic BDNF gene expression. However, the effects of long-term hyperglycemia and/or hyperinsulinemia on BDNF mRNA levels in the hypothalamus and other brain regions where BDNF regulates physiological functions have not been investigated. Therefore, using in situ hybridization we examined whether high glucose, high insulin, or both affected BDNF gene expression in vivo. Ovariectomized, estrogen-replaced adult rats were fitted with indwelling jugular catheters and infused for 48 h with: saline (control), glucose (hyperglycemia-hyperinsulinemia), glucose with insulin (hyperinsulinemia only), diazoxide (Dzx) (control), or glucose with Dzx (hyperglycemia only). Glucose infusion (Hyperglycemia and hyperinsulinemia) significantly increased BDNF mRNA expression in the posterior ventromedial nucleus of the hypothalamus (pVMH) and in the dorsomedial nucleus of the hypothalamus (DMH). Unexpectedly, infusion of the KATP channel opener Dzx also increased BDNF mRNA expression in the pVMH and DMH. In contrast, no significant changes in BDNF mRNA expression were observed in the groups that were hyperinsulinemic only or hyperglycemic only. BDNF mRNA expression did not differ as a function of treatment in the anterior VMH, paraventricular nucleus of the hypothalamus, the hippocampus, or the amygdala. Hyperglycemia with and without hyperinsulinemia decreased BDNF mRNA levels in the pituitary. Plasma BDNF concentrations were not changed by any of the treatments. Our results suggest that hyperinsulinemia alone does not affect BDNF mRNA expression in the hypothalamus, hippocampus, or pituitary. Our study is the first to distinguish that within the hypothalamus, prolonged high glucose levels in non-fasted rats regulates BDNF gene expression in a brain nuclei-specific fashion.

Developmental study of vitamin C distribution in children's brainstems by immunohistochemistry

Vitamin C (Vit C) is an important antioxidant, exerts powerful neuroprotective brain effects and plays a role in neuronal development and maturation. Vit C is present in brain tissue at higher concentrations than in other organs, but its detailed distribution in brain is unknown. Immunohistochemical detection of this vitamin has been performed by using a highly specific antibody against Vit C. The aim of the present work was to analyze the distribution of Vit C in children's brainstems during postnatal development, comparing two groups of ages: younger and older than one year of life. In general, the same areas showing neurons with Vit C in young cases are also immunostained at older ages. The distribution of neurons containing Vit C was broader in the brainstems of older children, suggesting that brainstem neurons maintain or even increase their ability to retain Vit C along the life span. Immunohistochemical labeling revealed only cell bodies containing this vitamin, and no immunoreactive fibers were observed. The distribution pattern of Vit C in children's brainstems suggests a possible role of Vit C in brain homeostatic regulation. In addition, the constant presence of Vit C in neurons of locus coeruleus supports the important role of Vit C in noradrenaline synthesis, which seemed to be maintained along postnatal development.