ABSTRACT
During central nervous system (CNS) development, neural progenitor cells (NPCs) generate neurons and glia in two different ways. In direct neurogenesis, daughter cells differentiate directly into neurons or glia, whereas in indirect neurogenesis, neurons or glia are generated after one or more daughter cell divisions. Intriguingly, indirect neurogenesis is not stochastically deployed and plays instructive roles during CNS development: increased generation of cells from specific lineages; increased generation of early or late-born cell types within a lineage; and increased cell diversification. Increased indirect neurogenesis might contribute to the anterior CNS expansion evident throughout the Bilateria and help to modify brain-region size without requiring increased NPC numbers or extended neurogenesis. Increased indirect neurogenesis could be an evolutionary driver of the gyrencephalic (that is, folded) cortex that emerged during mammalian evolution and might even have increased during hominid evolution. Thus, selection of indirect versus direct neurogenesis provides a powerful developmental and evolutionary instrument that drives not only the evolution of CNS complexity but also brain expansion and modulation of brain-region size, and thereby the evolution of increasingly advanced cognitive abilities. This Review describes indirect neurogenesis in several model species and humans, and highlights some of the molecular genetic mechanisms that control this important process.
Subject(s)
Neurogenesis , Neurogenesis/physiology , Humans , Animals , Biological Evolution , Neural Stem Cells/physiology , Neural Stem Cells/cytology , Neurons/physiology , Cell Differentiation/physiology , Central Nervous System/physiology , Central Nervous System/growth & development , Central Nervous System/cytology , Neuroglia/physiology , Brain/physiology , Brain/growth & development , Brain/cytologyABSTRACT
Microribonucleic acids (miRNAs) comprising miR-23a/b clusters, specifically miR-23a and miR-27a, are recognized for their divergent roles in myelination within the central nervous system. However, cluster-specific miRNA functions remain controversial as miRNAs within the same cluster have been suggested to function complementarily. This study aims to clarify the role of miR-23a/b clusters in myelination using mice with a miR-23a/b cluster deletion (KO mice), specifically in myelin expressing proteolipid protein (PLP). Inducible conditional KO mice were generated by crossing miR-23a/b clusterflox/flox mice with PlpCre-ERT2 mice; the offspring were injected with tamoxifen at 10 days or 10 weeks of age to induce a myelin-specific miR-23a/b cluster deletion. Evaluation was performed at 10 weeks or 12 months of age and compared with control mice that were not treated with tamoxifen. KO mice exhibit impaired motor function and hypoplastic myelin sheaths in the brain and spinal cord at 10 weeks and 12 months of age. Simultaneously, significant decreases in myelin basic protein (MBP) and PLP expression occur in KO mice. The percentages of oligodendrocyte precursors and mature oligodendrocytes are consistent between the KO and control mice. However, the proportion of oligodendrocytes expressing MBP is significantly lower in KO mice. Moreover, changes in protein expression occur in KO mice, with increased leucine zipper-like transcriptional regulator 1 expression, decreased R-RAS expression, and decreased phosphorylation of extracellular signal-regulated kinases. These findings highlight the significant influence of miR-23a/b clusters on myelination during postnatal growth and aging.
Subject(s)
Aging , MicroRNAs , Myelin Sheath , Animals , MicroRNAs/genetics , MicroRNAs/metabolism , Mice , Myelin Sheath/metabolism , Myelin Sheath/genetics , Aging/genetics , Central Nervous System/metabolism , Central Nervous System/growth & development , Mice, Knockout , Myelin Proteolipid Protein/genetics , Myelin Proteolipid Protein/metabolism , Spinal Cord/metabolism , Spinal Cord/growth & development , Myelin Basic Protein/metabolism , Myelin Basic Protein/genetics , Oligodendroglia/metabolism , Brain/metabolism , Brain/growth & developmentABSTRACT
The Vps10p domain receptor SorCS2 is crucial for the development and function of the nervous system and essential for brain-derived neurotrophic factor (BDNF)-induced changes in neuronal morphology and plasticity. SorCS2 regulates the subcellular trafficking of the BDNF signaling receptor TrkB as well as selected neurotransmitter receptors in a manner that is dependent on the SorCS2 intracellular domain (ICD). However, the cellular machinery and adaptor protein (AP) interactions that regulate receptor trafficking via the SorCS2 ICD are unknown. We here identify four splice variants of human SorCS2 differing in the insertion of an acidic cluster motif and/or a serine residue within the ICD. We show that each variant undergoes posttranslational proteolytic processing into a one- or two-chain receptor, giving rise to eight protein isoforms, the expression of which differs between neuronal and nonneuronal tissues and is affected by cellular stressors. We found that the only variants without the serine were able to rescue BDNF-induced branching of SorCS2 knockout hippocampal neurons, while variants without the acidic cluster showed increased interactions with clathrin-associated APs AP-1, AP-2, and AP-3. Using yeast two-hybrid screens, we further discovered that all variants bound dynein light chain Tctex-type 3; however, only variants with an acidic cluster motif bound kinesin light chain 1. Accordingly, splice variants showed markedly different trafficking properties and localized to different subcellular compartments. Taken together, our findings demonstrate the existence of eight functional SorCS2 isoforms with differential capacity for interactions with cytosolic ligands dynein light chain Tctex-type 3 and kinesin light chain 1, which potentially allows cell-type specific SorCS2 trafficking and BDNF signaling.
Subject(s)
Alternative Splicing , Central Nervous System , Receptors, Cell Surface , Humans , Adaptor Proteins, Signal Transducing/metabolism , Alternative Splicing/physiology , Brain-Derived Neurotrophic Factor/genetics , Brain-Derived Neurotrophic Factor/metabolism , Dyneins/metabolism , Kinesins/metabolism , Protein Binding , Protein Isoforms/metabolism , Receptor, trkB/metabolism , Receptors, Cell Surface/metabolism , Central Nervous System/growth & development , Protein Processing, Post-Translational , Protein Transport/geneticsABSTRACT
To explore the application effect of aminophylline combined with caffeine citrate and GMs in the evaluation of neurodevelopmental treatment and follow-up in high-risk preterm infants. A retrospective analysis of 66 high-risk preterm infants admitted to Hengshui People's Hospital from January 2020 to June 2021 was conducted. The children who received only conventional treatment were set as the control group, while those who received aminophylline and caffeine citrate on the basis of conventional treatment were set as the experimental group, 33 cases each group; GMs were used to evaluate the neurodevelopmental function of the children, and the treatment effect was analyzed. The normal proportion of GMs assessment results in the twisting phase and restless movement phase of the experimental group was superior to the control group (P<0.05); The proportion of children with normal neurodevelopment in the experimental group was significantly higher than that in the control group (P<0.05). Aminophylline in combination with caffeine citrate can help promote the neurodevelopment of children and improve their physical health using GMs assessment in the treatment and follow-up of high-risk preterm infants.
Subject(s)
Aminophylline/therapeutic use , Caffeine/therapeutic use , Central Nervous System/drug effects , Central Nervous System/growth & development , Child Development/drug effects , Citrates/therapeutic use , Aminophylline/administration & dosage , Cardiotonic Agents/administration & dosage , Cardiotonic Agents/therapeutic use , Central Nervous System Stimulants/administration & dosage , Central Nervous System Stimulants/therapeutic use , Humans , Infant , Infant, Premature , Motor ActivityABSTRACT
The function of poly(ADP-ribosyl) polymerase 1 (PARP1) in myelination and remyelination of the central nervous system (CNS) remains enigmatic. Here, we report that PARP1 is an intrinsic driver for oligodendroglial development and myelination. Genetic PARP1 depletion impairs the differentiation of oligodendrocyte progenitor cells (OPCs) into oligodendrocytes and impedes CNS myelination. Mechanistically, PARP1-mediated PARylation activity is not only necessary but also sufficient for OPC differentiation. At the molecular level, we identify the RNA-binding protein Myef2 as a PARylated target, which controls OPC differentiation through the PARylation-modulated derepression of myelin protein expression. Furthermore, PARP1's enzymatic activity is necessary for oligodendrocyte and myelin regeneration after demyelination. Together, our findings suggest that PARP1-mediated PARylation activity may be a potential therapeutic target for promoting OPC differentiation and remyelination in neurological disorders characterized by arrested OPC differentiation and remyelination failure such as multiple sclerosis.
Subject(s)
Cell Differentiation , Central Nervous System/metabolism , Myelin Sheath/metabolism , Poly (ADP-Ribose) Polymerase-1/metabolism , Poly ADP Ribosylation/physiology , Animals , Cell Survival/drug effects , Central Nervous System/growth & development , Cuprizone/pharmacology , Female , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Multiple Sclerosis/chemically induced , Multiple Sclerosis/metabolism , Multiple Sclerosis/pathology , Myelin Sheath/genetics , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Oligodendrocyte Precursor Cells/cytology , Oligodendrocyte Precursor Cells/metabolism , Oligodendrocyte Transcription Factor 2/deficiency , Oligodendrocyte Transcription Factor 2/genetics , Oligodendrocyte Transcription Factor 2/metabolism , Oligodendroglia/cytology , Oligodendroglia/metabolism , Oligodendroglia/physiology , Poly (ADP-Ribose) Polymerase-1/deficiency , Poly (ADP-Ribose) Polymerase-1/genetics , RNA/metabolism , Remyelination/drug effects , Repressor Proteins/genetics , Repressor Proteins/metabolismABSTRACT
BACKGROUND: There is increasing evidence regarding the influence of the intestinal microbiota on the disease processes of various organs and systems. Dysbiosis, that is, alteration of the composition and function of the microbiota may constitute an important risk factor for the development of mental disorders, namely, schizophrenia. OBJECTIVE: This works aims to review current evidence regarding the pathological mechanisms leading from dysbiosis to schizophrenia and in particular the deficit syndrome in schizophrenia. METHODS: Scientific articles from PubMed, SCOPUS, EMBASE, and Web of Science Core Collection published between September 2017 and December 2020 were included in this review. RESULTS: The commensal intestinal flora plays an important role in neurodevelopment. In the presence of dysbiosis, this maturation gets disturbed, resulting in the modification of brain structures and inflammatory responses at the intestinal, systemic, and Central Nervous System (CNS) levels. These disturbances may be linked to the development of symptoms of the disease. The microbiota exerts its influence on the CNS through several pathways, however, in this paper we focused on the membrane hypothesis and the inflammatory hypothesis. We explored the evidence concerning the use of probiotics, prebiotics, and fecal transplants. CONCLUSION: Although there is no consensus regarding the alterations that could constitute a risk factor for schizophrenia, some of the species appear to be more frequently altered, and their relationship with the host is dysregulated in patients at risk and with established schizophrenia, particularly in deficit schizophrenia.
Subject(s)
Brain/metabolism , Dysbiosis/complications , Gastrointestinal Microbiome/physiology , Inflammation/metabolism , Schizophrenia/etiology , Central Nervous System/growth & development , Central Nervous System/metabolism , Dysbiosis/metabolism , Fecal Microbiota Transplantation , Humans , Intestines/microbiology , Prebiotics , Probiotics/metabolismABSTRACT
BACKGROUND & AIMS: Preterm infants are at increased risk of long-term neurodevelopmental disabilities (NDD). Long chain n-3 fatty acids play a key role during the development of the central nervous system and some studies in preterm infants showed benefits of docosahexaenoic acid and arachidonic acid supplementation for visual and cognitive development. In recent years fish oil has been added to the fat blend of intravenous (IV) lipid emulsions (LE) but to date scanty data are available on neurodevelopmental outcome of preterm infants that received fish oil containing LE. We studied the effect of fish oil containing IV LE vs standard IV LE on neurodevelopment in a large cohort of preterm infants who received routine parenteral nutrition (PN) from birth. METHODS: We retrospectively reviewed the neurodevelopmental outcome of 477 preterm infants (birth weight (BW): 400-1249 g and gestational age (GA) at birth: 24+0 - 35+6 weeks (W)) admitted to our NICU between Oct-2008 and June-2017, who received routine PN with different LE, with and without fish oil (IV-FO vs CNTR). We compared neurodevelopment at 2 years corrected age by the Bayley III development scale and the incidence of NDD. RESULTS: Demographics, birth data and the incidence of the main clinical short-term outcomes of prematurity were similar in the two groups (IV-FO: n = 178, GA 197 ± 14 days, BW 931 ± 182 g; CNTR: n = 192, GA 198 ± 15 days, BW 944 ± 194 g). No differences were found in maternal demographics nor in parental education between the two groups. Cognitive score was not significantly different between IV-FO and CNTR (92 ± 15 vs 93 ± 13, p = 0.5). No differences were found in motor and language scores, and in the incidence of NDD in the two groups. CONCLUSIONS: Contrary to our hypothesis, the use of fish oil containing LE in a large cohort of preterm infants on routine PN did not result in better neurodevelopment. Large randomized controlled trials powered for neurodevelopment are needed to clarify the impact of the widely used fish oil containing LE on neurodevelopment of preterm infants.
Subject(s)
Central Nervous System/growth & development , Child Development/drug effects , Fish Oils/administration & dosage , Infant, Extremely Low Birth Weight , Infant, Premature , Parenteral Nutrition , Central Nervous System/drug effects , Humans , Infant, Newborn , Retrospective StudiesABSTRACT
Regenerative failure in the mammalian optic nerve is generally attributed to axotomy-induced retinal ganglion cell (RGC) death, an insufficient intrinsic regenerative capacity, and an extrinsic inhibitory environment. Here, we show that a chemoattractive CXCL12/CXCR4-dependent mechanism prevents the extension of growth-stimulated axons into the distal nerve. The chemokine CXCL12 is chemoattractive toward axonal growth cones in an inhibitory environment, and these effects are entirely abolished by the specific knockout of its receptor, CXCR4 (CXCR4-/-), in cultured regenerating RGCs. Notably, 8% of naïve RGCs express CXCL12 and transport the chemokine along their axons in the nerve. Thus, axotomy causes its release at the injury site. However, most osteopontin-positive α-RGCs, the main neuronal population that survives optic nerve injury, express CXCR4 instead. Thus, CXCL12-mediated attraction prevents growth-stimulated axons from regenerating distally in the nerve, indicated by axons returning to the lesion site. Accordingly, specific depletion of CXCR4 in RGC reduces aberrant axonal growth and enables long-distance regeneration. Likewise, CXCL12 knockout in RGCs fully mimics these CXCR4-/- effects. Thus, active CXCL12/CXCR4-mediated entrapment of regenerating axons to the injury site contributes to regenerative failure in the optic nerve.
Subject(s)
Axons/physiology , Chemokine CXCL12/genetics , Nerve Regeneration/genetics , Receptors, CXCR4/genetics , Animals , Axons/pathology , Axotomy , Central Nervous System/growth & development , Chemotactic Factors/genetics , Disease Models, Animal , Humans , Mice , Optic Nerve/growth & development , Optic Nerve/pathology , Optic Nerve Injuries/genetics , Optic Nerve Injuries/pathology , Retinal Ganglion Cells/metabolism , Retinal Ganglion Cells/pathologyABSTRACT
As a broad-spectrum with low toxicity, procymidone (PCM), is widely used in agriculture and frequently observed in aquatic system, which may cause some impacts on aquatic organisms. Here, to determine the developmental toxicity of PCM, embryonic and larval zebrafish were exposed to PCM at 0, 1, 10, 100 µg/L in dehydrogenated natural water containing 0.01% acetone for 7 days. The results showed that high concentration of PCM could cause the pericardial edema and increase the heart rates in larval zebrafish, suggesting that PCM had developmental toxicity to zebrafish. We also observed that PCM exposure not only changed the physiological parameters including TBA, GLU and pyruvic acid, but also changed the transcriptional levels of glycolipid metabolism related genes. In addition, after transcriptomics analysis, a total of 1065 differentially expressed genes, including 456 up-regulated genes and 609 down-regulated genes, changed significantly in 100 µg/L PCM treated larval zebrafish. Interestingly, after GO (Gene Ontology) analysis, the different expression genes (DEGs) were mainly enriched to the three different biology processes including GABA-nervous, lipid Metabolism and response to drug. We also observed that the levels of GABA receptor related genes including gabrg2, gabbr1α, gabbr1 and gabra6α were inhibited by PCM exposure. Interestingly, the swimming distance of larval zebrafish had the tendency to decrease after PCM exposure, indicating that the nervous system was affected by PCM. Taken together, the results confirmed that the fungicide PCM could cause developmental toxicity by influencing the lipid metabolism and GABA mediated nervous system and behavior in larval zebrafish. We believed that the results could provide an important data for the influence of PCM on aquatic animals.
Subject(s)
Bridged Bicyclo Compounds/toxicity , Fungicides, Industrial/toxicity , Gene Expression Regulation, Developmental/drug effects , Transcriptome/drug effects , Water Pollutants, Chemical/toxicity , Animals , Bridged Bicyclo Compounds/administration & dosage , Central Nervous System/drug effects , Central Nervous System/growth & development , Dose-Response Relationship, Drug , Larva/drug effects , Toxicity Tests , ZebrafishABSTRACT
Ascidians are invertebrate chordates and the closest living relative to vertebrates. In ascidian embryos a large part of the central nervous system arises from cells associated with mesoderm rather than ectoderm lineages. This seems at odds with the traditional view of vertebrate nervous system development which was thought to be induced from ectoderm cells, initially with anterior character and later transformed by posteriorizing signals, to generate the entire anterior-posterior axis of the central nervous system. Recent advances in vertebrate developmental biology, however, show that much of the posterior central nervous system, or spinal cord, in fact arises from cells that share a common origin with mesoderm. This indicates a conserved role for bi-potential neuromesoderm precursors in chordate CNS formation. However, the boundary between neural tissue arising from these distinct neural lineages does not appear to be fixed, which leads to the notion that anterior-posterior patterning and neural fate formation can evolve independently.
Subject(s)
Central Nervous System/growth & development , Urochordata/embryology , Animals , Body Patterning , Cell Lineage , Ectoderm/growth & development , Gene Expression Regulation, Developmental , Mesoderm/growth & development , Urochordata/growth & developmentABSTRACT
Iron-fortified formulas and iron drops (both usually ferrous sulfate, FS) prevent early life iron deficiency, but may delay growth and adversely affect neurodevelopment by providing excess iron. We used a rat pup model to investigate iron status, growth, and development outcomes following daily iron supplementation (10 mg iron/kg body weight, representative of iron-fortified formula levels) with FS or an alternative, bioavailable form of iron, ferrous bis-glycinate chelate (FC). On postnatal day (PD) 2, sex-matched rat litters (n = 3 litters, 10 pups each) were randomly assigned to receive FS, FC, or vehicle control until PD 14. On PD 15, we evaluated systemic iron regulation and CNS mineral interactions and we interrogated iron loading outcomes in the hippocampus, in search of mechanisms by which iron may influence neurodevelopment. Body iron stores were elevated substantially in iron-supplemented pups. All pups gained weight normally, but brain size on PD 15 was dependent on iron source. This may have been associated with reduced hippocampal oxidative stress but was not associated with CNS mineral interactions, iron regulation, or myelination, as these were unchanged with iron supplementation. Additional studies are warranted to investigate iron form effects on neurodevelopment so that iron recommendations can be optimized for all infants.
Subject(s)
Central Nervous System/growth & development , Dietary Supplements , Ferrous Compounds/pharmacology , Glycine/pharmacology , Iron Chelating Agents/pharmacology , Iron/metabolism , Iron/pharmacology , Animals , Animals, Newborn , Central Nervous System/drug effects , Gene Expression Regulation/drug effects , Hippocampus/drug effects , Hippocampus/metabolism , Homeostasis/drug effects , Iron/blood , Myelin Sheath/metabolism , Oxidative Stress/drug effects , Rats, Sprague-Dawley , Trace Elements/analysis , Weight Gain/drug effectsABSTRACT
Research on the development of the dorsal neural tube is particularly challenging. In this highly dynamic domain, a temporal transition occurs between early neural crest progenitors that undergo an epithelial-to-mesenchymal transition and exit the neural primordium, and the subsequent roof plate, a resident epithelial group of cells that constitutes the dorsal midline of the central nervous system. Among other functions, the roof plate behaves as an organizing center for the generation of dorsal interneurons. Despite extensive knowledge of the formation, emigration and migration of neural crest progenitors, little is known about the mechanisms leading to the end of neural crest production and the transition into a roof plate stage. Are these two mutually dependent or autonomously regulated processes? Is the generation of roof plate and dorsal interneurons induced by neural tube-derived factors throughout both crest and roof plate stages, respectively, or are there differences in signaling properties and responsiveness as a function of time? In this review, we discuss distinctive characteristics of each population and possible mechanisms leading to the shift between the above cell types.
Subject(s)
Cell Differentiation/genetics , Central Nervous System/growth & development , Neural Crest/growth & development , Neural Tube/growth & development , Animals , Bone Morphogenetic Proteins/genetics , Central Nervous System/metabolism , Embryonic Development/genetics , Gene Expression Regulation, Developmental/genetics , Interneurons/metabolism , Signal Transduction/genetics , Wnt Proteins/geneticsABSTRACT
ELAV/Hu factors are conserved RNA binding proteins (RBPs) that play diverse roles in mRNA processing and regulation. The founding member, Drosophila Elav, was recognized as a vital neural factor 35 years ago. Nevertheless, little was known about its impacts on the transcriptome, and potential functional overlap with its paralogs. Building on our recent findings that neural-specific lengthened 3' UTR isoforms are co-determined by ELAV/Hu factors, we address their impacts on splicing. While only a few splicing targets of Drosophila are known, ectopic expression of each of the three family members (Elav, Fne and Rbp9) alters hundreds of cassette exon and alternative last exon (ALE) splicing choices. Reciprocally, double mutants of elav/fne, but not elav alone, exhibit opposite effects on both classes of regulated mRNA processing events in larval CNS. While manipulation of Drosophila ELAV/Hu RBPs induces both exon skipping and inclusion, characteristic ELAV/Hu motifs are enriched only within introns flanking exons that are suppressed by ELAV/Hu factors. Moreover, the roles of ELAV/Hu factors in global promotion of distal ALE splicing are mechanistically linked to terminal 3' UTR extensions in neurons, since both processes involve bypass of proximal polyadenylation signals linked to ELAV/Hu motifs downstream of cleavage sites. We corroborate the direct action of Elav in diverse modes of mRNA processing using RRM-dependent Elav-CLIP data from S2 cells. Finally, we provide evidence for conservation in mammalian neurons, which undergo broad programs of distal ALE and APA lengthening, linked to ELAV/Hu motifs downstream of regulated polyadenylation sites. Overall, ELAV/Hu RBPs orchestrate multiple broad programs of neuronal mRNA processing and isoform diversification in Drosophila and mammalian neurons.
Subject(s)
Alternative Splicing/genetics , Cell Differentiation/genetics , Drosophila Proteins/genetics , ELAV Proteins/genetics , ELAV-Like Protein 1/genetics , Neurons/metabolism , 3' Untranslated Regions/genetics , Animals , Central Nervous System/growth & development , Central Nervous System/metabolism , Humans , Larva/genetics , Larva/growth & development , Nerve Tissue Proteins/genetics , Polyadenylation/genetics , RNA Processing, Post-Transcriptional/genetics , RNA, Messenger/genetics , RNA-Binding Proteins/genetics , Transcriptome/geneticsABSTRACT
Microglia are immune cells resident in the central nervous system (CNS). It has been gradually clarified that microglia play various roles at the developmental stage of the CNS. From embryonic to early postnatal age, microglia remove apoptotic cells by phagocytosis and refine the neural circuits by synaptic pruning. In addition, microglia promote the proliferation and differentiation of neural stem cells by releasing physiologically active substances. Our group has focused on the physiological actions of microglia via cytokines and chemokines at the early postnatal developmental stage. We found that a large number of activated microglia accumulate in the early postnatal subventricular zone (SVZ). We demonstrated that the these SVZ microglia facilitate neurogenesis and oligodendrogenesis via inflammatory cytokines including IL-1ß, TNFα, IL-6, IFNγ. We have also found that microglia regulate the functional maturation of the blood brain barrier (BBB) and identified the cytokines and chemokines involved in the effects of microglia. These findings indicate that microglia are physiologically more important than ever thought to reveal robust brain functions. Furthermore, the new mode of microglial action may lead to the discovery of drug targets of the incurable CNS diseases.
Subject(s)
Central Nervous System/embryology , Central Nervous System/growth & development , Chemokines/metabolism , Cytokines/metabolism , Microglia/immunology , Microglia/physiology , Animals , Apoptosis/immunology , Blood-Brain Barrier/embryology , Blood-Brain Barrier/growth & development , Cell Differentiation , Cell Proliferation , Chemokines/physiology , Cytokines/physiology , Humans , Inflammation Mediators/metabolism , Neural Stem Cells/physiology , Neurogenesis , Neuronal Plasticity/physiology , PhagocytosisABSTRACT
Mutations in the lysine demethylase 5 (KDM5) family of transcriptional regulators are associated with intellectual disability, yet little is known regarding their spatiotemporal requirements or neurodevelopmental contributions. Utilizing the mushroom body (MB), a major learning and memory center within the Drosophila brain, we demonstrate that KDM5 is required within ganglion mother cells and immature neurons for proper axogenesis. Moreover, the mechanism by which KDM5 functions in this context is independent of its canonical histone demethylase activity. Using in vivo transcriptional and binding analyses, we identify a network of genes directly regulated by KDM5 that are critical modulators of neurodevelopment. We find that KDM5 directly regulates the expression of prospero, a transcription factor that we demonstrate is essential for MB morphogenesis. Prospero functions downstream of KDM5 and binds to approximately half of KDM5-regulated genes. Together, our data provide evidence for a KDM5-Prospero transcriptional axis that is essential for proper MB development.
Subject(s)
Drosophila Proteins/metabolism , Histone Demethylases/metabolism , Mushroom Bodies/metabolism , Nerve Tissue Proteins/metabolism , Nuclear Proteins/metabolism , Transcription Factors/metabolism , Animals , Central Nervous System/growth & development , Central Nervous System/metabolism , Drosophila/genetics , Drosophila/metabolism , Drosophila Proteins/genetics , Drosophila melanogaster/genetics , Drosophila melanogaster/metabolism , Gene Expression Regulation, Developmental , Histone Demethylases/genetics , Larva/growth & development , Larva/metabolism , Mutation , Nerve Tissue Proteins/genetics , Neurons/metabolism , Nuclear Proteins/genetics , Transcription Factors/geneticsABSTRACT
During restricted time windows of postnatal life, called critical periods, neural circuits are highly plastic and are shaped by environmental stimuli. In several mammalian brain areas, from the cerebral cortex to the hippocampus and amygdala, the closure of the critical period is dependent on the formation of perineuronal nets. Perineuronal nets are a condensed form of an extracellular matrix, which surrounds the soma and proximal dendrites of subsets of neurons, enwrapping synaptic terminals. Experimentally disrupting perineuronal nets in adult animals induces the reactivation of critical period plasticity, pointing to a role of the perineuronal net as a molecular brake on plasticity as the critical period closes. Interestingly, in the adult brain, the expression of perineuronal nets is remarkably dynamic, changing its plasticity-associated conditions, including memory processes. In this review, we aimed to address how perineuronal nets contribute to the maturation of brain circuits and the regulation of adult brain plasticity and memory processes in physiological and pathological conditions.
Subject(s)
Brain/physiology , Extracellular Matrix , Neuronal Plasticity , Animals , Brain/growth & development , Central Nervous System/growth & development , Central Nervous System/physiology , Critical Period, Psychological , HumansABSTRACT
Eukaryotes have evolved a variety of mRNA surveillance mechanisms to detect and degrade aberrant mRNAs with potential deleterious outcomes. Among them, nonsense-mediated mRNA decay (NMD) functions not only as a quality control mechanism targeting aberrant mRNAs containing a premature termination codon but also as a posttranscriptional gene regulation mechanism targeting numerous physiological mRNAs. Despite its well-characterized molecular basis, the regulatory scope and biological functions of NMD at an organismal level are incompletely understood. In humans, mutations in genes encoding core NMD factors cause specific developmental and neurological syndromes, suggesting a critical role of NMD in the central nervous system. Here, we review the accumulating biochemical and genetic evidence on the developmental regulation and physiological functions of NMD as well as an emerging role of NMD dysregulation in neurodegenerative diseases.
Subject(s)
Central Nervous System/growth & development , Gene Expression Regulation, Developmental , Neurodevelopmental Disorders/genetics , Nonsense Mediated mRNA Decay , Animals , Codon, Nonsense , Humans , Mutation , Protein Biosynthesis/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolismABSTRACT
Milk contains about 4% fat globules with its surface covered by polar lipids. Despite the abundant consumption of dairy products, the biological effects of dietary milk polar lipids on metabolic health have only been sparsely examined. Maternal obesity results in neurodevelopmental disorders and cognitive impairment in offspring. Considering the importance of maternal nutrition, the effects of polar lipids-enriched milk fat globule membrane (MFGM-PL) supplementation to dams during pregnancy and lactation on neurodevelopment and its long-term programming effects on offspring cognition were examined. Female Sprague-Dawley rats consumed 8-week control diet (CON) or high-fat diet (HFD) to induce obesity before mating. Then, female rats were fed CON or HFD with or without the supplementation of 400 mg/kg body weight MFGM-PL during pregnancy and lactation. The offspring were fed 11-week HFD after weaning. MFGM-PL supplementation to obese dams suppressed body weight gain and hyperinsulinemia in both dams and offspring. Offspring born to obese dams displayed delayed neurological reflexes development, impaired neurogenesis before weaning, and cognitive impairment in adulthood, which were recovered by maternal MFGM-PL supplementation. Insulin resistance and aberrant brain-derived neurotrophic factor signaling were induced in the hippocampus of neonatal and adult offspring due to maternal and progeny HFD, but recovered by maternal MFGM-PL administration. This study demonstrates that maternal MFGM-PL supplementation can promote neurodevelopment and exert long-term effects against HFD-induced cognitive impairment in offspring via alleviating hippocampal insulin resistance. Hence, MFGM-PL is a promising ingredient for exerting beneficial programming effects on the brain health of offspring.
Subject(s)
Central Nervous System/growth & development , Cognition/drug effects , Dietary Supplements , Lipids/pharmacology , Milk/chemistry , Obesity , Animals , Brain-Derived Neurotrophic Factor/genetics , Brain-Derived Neurotrophic Factor/metabolism , Cyclic AMP Response Element-Binding Protein/genetics , Cyclic AMP Response Element-Binding Protein/metabolism , Diet, High-Fat/adverse effects , Female , Gene Expression Regulation, Developmental/drug effects , Lipids/administration & dosage , Male , Pregnancy , Prenatal Nutritional Physiological Phenomena , Rats , Rats, Sprague-Dawley , Receptor, trkB/genetics , Receptor, trkB/metabolismABSTRACT
The neural tube is the first critically important structure that develops in the embryo. It serves as the primordium of the central nervous system; therefore, the proper formation of the neural tube is essential to the developing organism. Neural tube defects (NTDs) are severe congenital defects caused by failed neural tube closure during early embryogenesis. The pathogenesis of NTDs is complicated and still not fully understood even after decades of research. While it is an ethically impossible proposition to investigate the in vivo formation process of the neural tube in human embryos, a newly developed technology involving the creation of neural tube organoids serves as an excellent model system with which to study human neural tube formation and the occurrence of NTDs. Herein we reviewed the recent literature on the process of neural tube formation, the progress of NTDs investigations, and particularly the exciting potential to use neural tube organoids to model the cellular and molecular mechanisms underlying the etiology of NTDs.
Subject(s)
Central Nervous System/growth & development , Embryo, Mammalian/metabolism , Neural Tube Defects/etiology , Neural Tube/metabolism , Organoids/pathology , Animals , Disease Models, Animal , Embryo, Mammalian/pathology , Humans , Neural Tube/pathology , Neural Tube Defects/metabolism , Organoids/growth & developmentABSTRACT
The zinc finger-containing transcription factor Gli3 is a key mediator of Hedgehog (Hh) signaling pathway. In vertebrates, Gli3 has widespread expression pattern during early embryonic development. Along the anteroposterior axes of the central nervous system (CNS), dorsoventral neural pattern elaboration is achieved through Hh mediated spatio-temporal deployment of Gli3 transcripts. Previously, we and others uncovered a set of enhancers that mediate many of the known aspects of Gli3 expression during neurogenesis. However, the potential role of Gli3 associated enhancers in trait evolution has not yet received any significant attention. Here, we investigate the evolutionary patterns of Gli3 associated CNS-specific enhancers that have been reported so far. A subset of these enhancers has undergone an accelerated rate of molecular evolution in the human lineage in comparison to other primates/mammals. These fast-evolving enhancers have acquired human-specific changes in transcription factor binding sites (TFBSs). These human-unique changes within subset of Gli3 associated CNS-specific enhancers were further validated as single nucleotide polymorphisms through 1000 Genome Project Phase 3 data. This work not only infers the molecular evolutionary patterns of Gli3 associated enhancers but also provides clues for putative genetic basis of the population-specificity of gene expression regulation.