RACK1 regulates neural development

Receptor for activated C kinase 1（RACK1）is an evolutionarily conserved scaffolding protein within the tryptophan-aspartate（WD）repeat family of proteins.RACK1 can bind multiple signaling molecules concurrently,as well as stabilize and anchor proteins.RACK1 also plays an important role at focal adhesions,where it acts to regulate cell migration.In addition,RACK1 is a ribosomal binding protein and thus,regulates translation.Despite these numerous functions,little is known about how RACK1 regulates nervous system development.Here,we review three studies that examine the role of RACK1 in neural development.In brief,these papers demonstrate that（1）RACK-1,the C.elegans homolog of mammalian RACK1,is required for axon guidance;（2）RACK1 is required for neurite extension of neuronally differentiated rat PC12cells;and（3）RACK1 is required for axon outgrowth of primary mouse cortical neurons.Thus,it is evident that RACK1 is critical for appropriate neural development in a wide range of species,and future discoveries could reveal whether RACK1 and its signaling partners are potential targets for treatment of neurodevelopmental disorders or a therapeutic approach for axonal regeneration.

Influence of Sox protein SUMOylation on neural development and regeneration

SRY-related HMG-box(Sox) transcription factors are known to regulate central nervous system development and are involved in several neurological diseases.Post-translational modification of Sox proteins is known to alter their functions in the central nervous system.Among the different types of post-translational modification,small ubiquitin-like modifier(SUMO) modification of Sox proteins has been shown to modify their transcriptional activity.Here,we review the mechanisms of three Sox proteins in neuronal development and disease,along with their transcriptional changes under SUMOylation.Across three species,lysine is the conserved residue for SUMOylation.In Drosophila,SUMOylation of Sox N plays a repressive role in transcriptional activity,which impairs central nervous system development.However,de SUMOylation of Sox E and Sox11 plays neuroprotective roles,which promote neural crest precursor formation in Xenopus and retinal ganglion cell differentiation as well as axon regeneration in the rodent.We further discuss a potential translational therapy by SUMO site modification using AAV gene transduction and Clustered regularly interspaced short palindromic repeats-Cas9 technology.Understanding the underlying mechanisms of Sox SUMOylation,especially in the rodent system,may provide a therapeutic strategy to address issues associated with neuronal development and neurodegeneration.

Influencing factors of colostrum exposure to low-level lead and their relationship with early neural development of infants

BACKGROUND： Exposure to low-level lead has a toxic effect on the development of neonates, which has attracted wide attention. Colostrum lead level can be used as the indication of lead exposure. OBJECTIVE： To observe the relationship of colostrum lead level and the neurobehavioral development of infants. DESIGN： A prospective control observation. SETTING： Center for Maternal and Child Health, Shanxi Provincial Children＇s Hospital. PARTICIPANTS： Totally 128 neonates of full-term normal delivery, 76 male and 52 female, from Shanxi Provincial Maternal and Child Health Center and Jiexiu Maternal and Child Health Center were involved in this study. All the involved neonates had no peripartal ischemic/hypoxic history or fetus intrauterine developmental lag. Pregnant women had no various acute and chronic diseases in pregnancy, family history of neurological disease or occupational lead exposure. 128 portions of colostrum sample of full-term normal delivery were collected. Informed consents of detected items were obtained from the puerperants and their relatives. METHODS： ① Experimental grouping： Lead level in the colostrum was determined by atomic absorption spectrometry. According to lead level in the colostrum, the neonates were classified into two exposure groups of greater than or equal to 0.24 μmol/L in a high-level lead group and less than 0.24 μ mol/L in a low-level lead group. ② Experimental evaluation： Mental developmental index （MDI） and psychological developmental index （PDI） of 3-month-old infants were evaluated with Bayley Scales of Infant Development （BSID）. The relationships of MDI, PDI and colostrum lead level were performed correlation regression analysis; The relationship of colostrum lead level and development was performed multi-factor analysis with family environment and health questionnaires. MAIN OUTCOME MEASURES： ① Evaluation results of MDI and PDI. ② Multi-factor analysis results. RESULTS： Totally 128 neonates were involved in the study. Ten and eleven neonates were lost due to emigration in the high-level lead group and low-level lead group respectively, and the other 107 neonates participated in the final analysis. ① MDI and PDI in the high-level lead group were significantly lower than those in the low-level lead group, respectively （P 〈 0.01）; Regression analysis results showed that two developmental indexes were statistically negatively correlated with colostrum lead level （regression equation y = 1.9＋0.01x1,-0.04x2,＋0.04x3,＋0.03x4）. ② Four variables of the factors included by family environment and health questionnaires were taken into equation. Large maternal age, irrational dietary pattern in pregnancy and pollution degree of habitation environment in pregnancy were the risk factors of colostrum lead level （partial regression coefficien t =0.598 4,0.426 8,0.306 7,P 〈 0.05-0.01）, and calcium supplementation in pregnancy was a protective factor （partial regression coefficien t =-0.455 8, P 〈 0.01）. CONCLUSION： High colostrum lead level will have adverse effects on the early development of neonates; Large maternal age, irrational dietary pattern in pregnancy and pollution degree of habitation environment in pregnancy are the risk factors of colostrum lead level, and calcium supplementation in pregnancy was a protective factor.

Matrix metalloproteinases in neural development:a phylogenetically diverse perspective

The matrix metalloproteinases（MMPs） are a family of zinc-dependent endopeptidases originally characterized as secreted proteases responsible for degrading extracellular matrix proteins.Their canonical role in matrix remodelling is of significant importance in neural development and regeneration,but emerging roles for MMPs,especially in signal transduction pathways,are also of obvious importance in a neural context.Misregulation of MMP activity is a hallmark of many neuropathologies,and members of every branch of the MMP family have been implicated in aspects of neural development and disease.However,while extraordinary research efforts have been made to elucidate the molecular mechanisms involving MMPs,methodological constraints and complexities of the research models have impeded progress.Here we discuss the current state of our understanding of the roles of MMPs in neural development using recent examples and advocate a phylogenetically diverse approach to MMP research as a means to both circumvent the challenges associated with specific model organisms,and to provide a broader evolutionary context from which to synthesize an understanding of the underlying biology.

Involvement of XZFP36L1,an RNA-binding protein,in Xenopus neural development

Xenopus ZFP36L1(zinc finger protein 36,C3H type-like 1)belongs to the ZFP36 family of RNA-binding proteins,which contains two characteristic tandem CCCH-type zinc-finger domains.The ZFP36 proteins can bind AU-rich elements in 3'untranslated regions of target mRNAs and promote their turnover.However,the expression and role of ZFP36 genes during neural development in Xenopus embryos remains largely unknown.The present study showed that Xenopus ZFP36L1 was expressed at the dorsal part of the forebrain,forebrain-midbrain boundary,and midbrain-hindbrain boundary from late neurula stages to tadpole stages of embryonic development.Overexpression of XZFP36L1 in Xenopus embryos inhibited neural induction and differentiation,leading to severe neural tube defects.The function of XZP36L1 requires both its zinc finger and C terminal domains,which also affect its subcellular localization.These results suggest that XZFP36L1 is likely involved in neural development in Xenopus and might play an important role in post-transcriptional regulation.

Involvement of XZFP36L1, an RNA-binding protein, in Xenopus neural development ＇

Xenopus ZFP36L1 （zinc finger protein 36, C3H type-like 1） belongs to the ZFP36 family of RNA-binding proteins, which contains two characteristic tandem CCCH-type zinc-finger domains. The ZFP36 proteins can bind AU-rich elements in 3＇ untranslated regions of target mRNAs and promote their turnover. However, the expression and role of ZFP36 genes during neural development in Xenopus embryos remains largely unknown. The present study showed that Xenopus ZFP36L1 was expressed at the dorsal part of the forebrain, forebrain-midbrain boundary, and midbrain-hindbrain boundary from late neurula stages to tadpole stages of embryonic development. Overexpression of XZFP36L1 in Xenopus embryos inhibited neural induction and differentiation, leading to severe neural tube defects. The function of XZP36L1 requires both its zinc finger and C terminal domains, which also affect its subcellular localization. These results suggest that XZFP36L1 is likely involved in neural development in Xenopus and might play an important role in post-transcriptional regulation.

Role of brahma-related gene 1/brahma-associated factor subunits in neural stem/progenitor cells and related neural developmental disorders

Different fates of neural stem/progenitor cells(NSPCs)and their progeny are determined by the gene regulatory network,where a chromatin-remodeling complex affects synergy with other regulators.Here,we review recent research progress indicating that the BRG1/BRM-associated factor(BAF)complex plays an important role in NSPCs during neural development and neural developmental disorders.Several studies based on animal models have shown that mutations in the BAF complex may cause abnormal neural differentiation,which can also lead to various diseases in humans.We discussed BAF complex subunits and their main characteristics in NSPCs.With advances in studies of human pluripotent stem cells and the feasibility of driving their differentiation into NSPCs,we can now investigate the role of the BAF complex in regulating the balance between self-renewal and differentiation of NSPCs.Considering recent progress in these research areas,we suggest that three approaches should be used in investigations in the near future.Sequencing of whole human exome and genome-wide association studies suggest that mutations in the subunits of the BAF complex are related to neurodevelopmental disorders.More insight into the mechanism of BAF complex regulation in NSPCs during neural cell fate decisions and neurodevelopment may help in exploiting new methods for clinical applications.

Function of pioneer neurons specified by the basic helix-loop-helix transcription factor atonal in neural development

Basic helix-loop-helix （bHLH） transcription factors regulate the differentiation of various tissues in a vast diversity of species. The bHLH protein Atonal was first identified as a proneural gene involved in the formation of mechanosensory cells and photoreceptor cells in Drosophila （larman et al., 1993, 1994）. Atonal is expressed in sensory organ precursors and is required and sufficient for the development of chordotonal organs （Jar- man et al., 1993）. Moreover, Atonal expression is observed in the developing eye and is essential for the differentiation of R8 photoreceptors, which are the first photoreceptors that appear during development. Atonal is not involved in the formation of other photoreceptors （R1-R7） directly. However, R8 photore- ceptors recruit other photoreceptors from the surrounding cells （Jarman et al., 1994）.

Down syndrome cell adhesion molecule and its functions in neural development

The nervous system is a complex network with many types of neurons and numerous synaptic connections.The present knowledge on how neurons recognize specific targets and form such an intricate network is still limited.The Down syndrome cell adhesion molecule （DSCAM） belongs to the immunoglobulin superfamily and contributes to defects in the central nervous system in Down syndrome patients.DSCAM plays important roles in neural development,including dendritic patterning and self-avoidance,axon guidance and branching,axon target recognition and synaptic formation.However,the functional mechanisms and the underlying signaling pathways are still largely unknown.Here the functions of DSCAM in neural development were reviewed.Future research for better understanding DSCAM function and the relevance of DSCAM to human diseases was also discussed.

Planar cell polarity genes, Celsr1-3, in neural development

flamingo is among the ＇core＇ planar cell-polarity genes, protein of which belongs to a unique cadherin subfamily. In contrast to the classic cadherins, composed of several extracellular cadherin repeats, one transmembrane domain and one cytoplasmic segment linked to catenin binding, Drosophila Flamingo has seven transmembrane segments and a cytoplasmic tail with no catenin-binding sequence. In Drosophila, Flamingo has pleotropic roles in controlling epithelial polarity and neuronal morphogenesis. Three mammalian orthologs of flamingo, Celsrl-3, are widely expressed in the nervous system. Recent work has shown that Celsrl-3 play important roles in neural development, such as in axon guidance, neuronal migration, and cilium polarity. CeIsrl-3 single-gene knockout mice exhibit different phenotypes, but there are cooperative interactions among these genes.

Ankfy1 is dispensable for neural stem/precursor cell development

There are few studies on the membrane protein Ankfyl. We have found Ankfyl is specifically expressed in neural stem/precursor cells during early development in mice （murine）. To further explore Ankfyl function in neural development, we developed a gene knockout mouse with a mixed Balb/C and C57/BL6 genetic background. Using immunofluorescence and in situ hybridization, neural defects were absent in mixed genetic Ankfyl null mice during development and in adults up to 2 months old. However, Ankfyl gene knockout mice with a pure genetic background were found to be lethal in the C57/BL6 inbred mice embryos, even after seven generations of backcrossing. Polymerase chain reaction confirmed homozygotes were unattainable as early as embryonic day 11.5. We conclude that Ankfyl protein is dispensable in neural stem/precursor ceils, but could be critical for early embryonic murine development, depending on the genetic background.

Apoptotic gene expression in the neural tube during early human embryonic development

Neural tube development comprises neural induction, neural epithelial cell proliferation, and apoptosis, as well as migration of nerve cells. Too much or too little apoptosis leads to abnormal nervous system development. The present study analyzed expression and distribution of apoptotic-related factors, including Fas, FasL, and caspase-3, during human embryonic neural tube development. Experimental results showed that increased caspase-3 expression promoted neural apoptosis via a mitochondrial-mediated intrinsic pathway at 4 weeks during early human embryonic neural tube development. Subsequently, Fas and FasL expression increased during embryonic development. The results suggest that neural cells influence neural apoptosis through synergistic effects of extrinsic pathways. Therefore, neural apoptosis during the early period of neural tube development in the human embryo might be regulated by the death receptor induced apoptotic extrinsic pathways.

A role for mitogen-activated protein kinase phosphatase 1(MKP1) in neural cell development and survival

The mitogen-activated protein kinase（MAPK）pathways are a group of conserved intracellular signalling pathways present in most cells including neurons and glia.These pathways respond to a variety of stimuli including growth factors,cytokines and oxidative stress to generate appropriate cellular responses such as modulation of gene expression,cell proliferation,differentiation and survival as well as the stress response（Korhonen and Moilanen,2014）.

Basic Research on Brain Development and Neural Plasticity Kicked Off

A major basic research projectin the field of neurosciencewas launched on November26 last year at the Shanghai-basedInstitute of Neuroscience of the Chi-nese Academy of Sciences(CAS).

Long noncoding RNAs in neurodevelopment and Parkinson’s disease

Long noncoding RNAs(lnc RNAs) are RNA molecules comprising more than 200 nucleotides, which are not translated into proteins. Many studies have shown that lnc RNAs are involved in regulating a variety of biological processes, including immune, cancer, stress, development and differentiation at the transcriptional, epigenetic or post-transcriptional levels. Here, we review the role of lnc RNAs in the process of neurodevelopment, neural differentiation, synaptic function, and pathogenesis of Parkinson’s disease(PD). These pathomechanisms include protein misfolding and aggregation, disordered protein degradation, mitochondrial dysfunction, oxidative stress, autophagy, apoptosis, and neuroinflammation. This information will provide the basis of lnc RNA-based disease diagnosis and drug treatment for PD.

Toxic effect of acrylamide on the development of hippocampal neurons of weaning rats

Although numerous studies have examined the neurotoxicity of acrylamide in adult animals,the effects on neuronal development in the embryonic and lactational periods are largely unknown.Thus,we examined the toxicity of acrylamide on neuronal development in the hippocampus of fetal rats during pregnancy.Sprague-Dawley rats were mated with male rats at a 1：1 ratio.Rats were administered 0,5,10 or 20 mg/kg acrylamide intragastrically from embryonic days 6–21.The gait scores were examined in pregnant rats in each group to analyze maternal toxicity.Eight weaning rats from each group were also euthanized on postnatal day 21 for follow-up studies.Nissl staining was used to observe histological change in the hippocampus.Immunohistochemistry was conducted to observe the condition of neurites,including dendrites and axons.Western blot assay was used to measure the expression levels of the specific nerve axon membrane protein,growth associated protein 43,and the presynaptic vesicle membrane specific protein,synaptophysin.The gait scores of gravid rats significantly increased,suggesting that acrylamide induced maternal motor dysfunction.The number of neurons,as well as expression of growth associated protein 43 and synaptophysin,was reduced with increasing acrylamide dose in postnatal day 21 weaning rats.These data suggest that acrylamide exerts dose-dependent toxic effects on the growth and development of hippocampal neurons of weaning rats.

Working-memory training improves developmental dyslexia in Chinese children

Although plasticity in the neural system underlies working memory, and working memory can be improved by training, there is thus far no evidence that children with developmental dyslexia can benefit from working-memory training. In the present study, thirty dyslexic children aged 8-11 years were recruited from an elementary school in Wuhan, China. They received working-memory training including training in visuospatial memory, verbal memory, and central executive tasks. The difficulty of the tasks was adjusted based on the performance of each subject, and the training sessions lasted 40 minutes per day, for 5 weeks. The results showed that working-memory training significantly enhanced performance on the nontrained working memory tasks such as the visuospatial, the verbal domains, and central executive tasks in children with developmental dyslexia. More importantly, the visual rhyming task and reading fluency task were also significantly improved by training. Progress on working memory measures was related to changes in reading skills. These experimental findings indicate that working memory is a pivotal factor in reading development among children with developmental dyslexia, and interventions to improve working memory may help dyslexic children to become more proficient in reading.

High-concentration sevoflurane exposure in mid-gestation induces apoptosis of neural stem cells in rat offspring

Sevoflurane is the most commonly used volatile anesthetic during pregnancy.The viability of neural stem cells directly affects the development of the brain.However,it is unknown whether the use of sevoflurane during the second trimester affects the survival of fetal neural stem cells.Therefore,in this study,we investigated whether exposure to sevoflurane in mid-gestation induces apoptosis of neural stem cells and behavioral abnormalities.On gestational day 14,pregnant rats were anesthetized with 2% or 3.5% sevoflurane for 2 hours.The offspring were weaned at 28 days and subjected to the Morris water maze test.The brains were harvested to examine neural stem cell apoptosis by immunofluorescence and to measure Nestin and SOX-2 levels by western blot assay at 6,24 and 48 hours after anesthesia as well as on postnatal day（P） 0,14 and 28.Vascular endothelial growth factor（VEGF） and phosphoinositide 3-kinase（PI3 K）/AKT pathway protein levels in fetal brain at 6 hours after anesthesia were assessed by western blot assay.Exposure to high-concentration（3.5%） sevoflurane during mid-gestation increased escape latency and path length to the platform,and it reduced the average duration spent in the target quadrant and platform crossing times.At 6,24 and 48 hours after anesthesia and at P0,P14 and P28,the percentage of Nestin/terminal deoxynucleotidyl transferase d UTP nick end labeling（TUNEL）-positive cells was increased,but Nestin and SOX-2 protein levels were decreased in the hippocampus of the offspring.At 6 hours after anesthesia,VEGF,PI3 K and phospho-AKT（p-AKT） levels were decreased in the fetal brain.These changes were not observed in animals given low-concentration（2%） sevoflurane exposure.Together,our findings indicate that exposure to a high concentration of sevoflurane（3.5%） in mid-gestation decreases VEGF,PI3 K and p-AKT protein levels and induces neural stem cell apoptosis,thereby causing learning and memory dysfunction in the offspring.

神经嵴发育异常相关眼病

神经嵴是一个动态的胚胎干细胞群体,在眼部发育中起着关键作用。神经嵴与周围的神经外胚层、表面外胚层和中胚层相互作用,发育成眼球及其附属器的多种组织结构,包括角膜基质及内皮、小梁网、虹膜基质、睫状肌、玻璃体和脉络膜血管、Müller细胞等。眼部神经嵴细胞迁移和发育异常会引起一系列复杂的眼部疾病,包括影响眼前段的疾病,如Axenfeld-Rieger综合征、Peters异常、无虹膜、原发性先天性青光眼和指甲-髌骨综合征,以及影响眼后段的缺陷性疾病,如CHARGE综合征和鳃-眼-面综合征,此外还有一些罕见的神经嵴疾病的眼部异常,如Waardenburg综合征、Treacher-Collins综合征和Char综合征等。在这里我们将神经嵴细胞发育异常导致的眼部相关疾病做一综述,探讨与神经嵴迁移和发育相关的基因,以及这些基因的突变和缺陷如何导致眼部疾病。

Lethal Developmental Defects: An Overview

About 3% of all conceptions are associated with major congenital malformations, many of them are lethal developmental defect and genetic in origin or teratogenic (adverse effects of the environment during gametogenesis or early embryogenesis). Genetics with or without adverse environment has role in virtually every developmental defect/malformation disorders in causation, predisposition, susceptibility & modulation of disease. Advances in genetics, introduction of triple marker screening, routine obstetric ultrasound examination into obstetric practice & accesses to prenatal diagnosis helped in secondary prevention (early detection & termination) of lethal developmental defects. Ultrasound detection of fetal developmental defects/malformation is common now and often decision on pregnancy solely based on ultrasonic morphological description. This practice leads to difficulty in providing accurate counseling as well as preventing disorder in subsequent pregnancy, in particular early. Hence an understanding of reproductive genetics of major developmental disorders is important for today’s perinatal care specialists. This overview will outline the various lethal developmental defects observed in an advanced reproductive genetics set up and various approaches adopted to derive diagnosis. Detailed assessment of fetus after termination of pregnancy (spontaneous/induced) for fetal anomalies was carried out in most cases. As most cases was referred after termination in formalin routine chromosomal analysis was not possible however, in selected cases targeted FISH analysis with specific chromosomal probe was carried out to confirm clinical diagnosis. Detailed evaluation of fetus is important as this practice often helped in modification of genetic counseling, as well as course of management in the next pregnancy. No molecular diagnostic or screening work was carried out due to non availability of information and facility in past. However, this is important today as many of the lethal developmental defects are yet to be categorized etiopathologically, and hence immediate need is to start clinical registry along with biorepository of developmental defects cases for future research work on informative families, in particular with multiple affected fetuses/sibs, using genomics, proteomics, metabolomics, platforms.