RESUMO
Neurogenesis in the developing and adult brain is intimately linked to remodeling of cellular metabolism. However, it is still unclear how distinct metabolic programs and energy sources govern neural stem cell (NSC) behavior and subsequent neuronal differentiation. Here, we found that adult mice lacking the mitochondrial urea metabolism enzyme, Arginase-II (Arg-II), exhibited NSC overactivation, thereby leading to accelerated NSC pool depletion and decreased hippocampal neurogenesis over time. Mechanistically, Arg-II deficiency resulted in elevated L-arginine levels and induction of a metabolic shift from glycolysis to oxidative phosphorylation (OXPHOS) caused by impaired attachment of hexokinase-I to mitochondria. Notably, selective inhibition of OXPHOS ameliorated NSC overactivation and restored abnormal neurogenesis in Arg-II deficient mice. Therefore, Arg-II-mediated intracellular L-arginine homeostasis directly influences the metabolic fitness of neural stem cells that is essential to maintain neurogenesis with age.
Assuntos
Células-Tronco Neurais , Camundongos , Animais , Proliferação de Células , Células-Tronco Neurais/metabolismo , Neurogênese/fisiologia , Glicólise , Homeostase , Arginina/metabolismoRESUMO
The circadian clock throughout the day organizes the activity of neural stem cells (NSCs) in the dentate gyrus (DG) of adult hippocampus temporally. However, it is still unclear whether and how circadian signals from the niches contribute to daily rhythmic variation of NSC activation. Here, we show that norepinephrinergic (NEergic) projections from the locus coeruleus (LC), a brain arousal system, innervate into adult DG, where daily rhythmic release of norepinephrine (NE) from the LC NEergic neurons controlled circadian variation of NSC activation through ß3-adrenoceptors. Disrupted circadian rhythmicity by acute sleep deprivation leads to transient NSC overactivation and NSC pool exhaustion over time, which is effectively ameliorated by the inhibition of the LC NEergic neuronal activity or ß3-adrenoceptors-mediated signaling. Finally, we demonstrate that NE/ß3-adrenoceptors-mediated signaling regulates NSC activation through molecular clock BMAL1. Therefore, our study unravels that adult NSCs precisely coordinate circadian neural circuit and intrinsic molecular circadian clock to adapt their cellular behavior across the day.
Assuntos
Relógios Circadianos , Células-Tronco Neurais , Humanos , Adulto , Ritmo Circadiano/fisiologia , Hipocampo , Relógios Circadianos/fisiologia , Receptores AdrenérgicosRESUMO
Autism is often comorbid with other psychiatric disorders. We have previously shown that Dip2a knockout (KO) induces autism-like behaviors in mice. However, the role of Dip2a in other psychiatric disorders remains unclear. In this paper, we revealed that Dip2a KO mice had comorbid anxiety. Dip2a KO led to a reduction in the dendritic length of cortical and hippocampal excitatory neurons. Molecular mechanism studies suggested that AMPK was overactivated and suppressed the mTOR cascade, contributing to defects in dendritic morphology. Deletion of Dip2a in adult-born hippocampal neurons (Dip2a conditional knockout (cKO)) increased susceptibility to anxiety upon acute stress exposure. Application of (2R,6R)-hydroxynorketamine (HNK), an inhibitor of mTOR, rescued anxiety-like behaviors in Dip2a KO and Dip2a cKO mice. In addition, 6 weeks of high-fat diet intake alleviated AMPK-mTOR signaling and attenuated the severity of anxiety in both Dip2a KO mice and Dip2a cKO mice. Taken together, these results reveal an unrecognized function of DIP2A in anxiety pathophysiology via regulation of AMPK-mTOR signaling.
Assuntos
Proteínas Quinases Ativadas por AMP , Transdução de Sinais , Camundongos , Animais , Camundongos Knockout , Serina-Treonina Quinases TOR/metabolismo , Ansiedade/genética , Proteínas NuclearesRESUMO
Multiciliated ependymal cells line the ventricle wall and generate CSF flow through ciliary beating. Defects in ependymal cells cause hydrocephalus; however, there are still significant gaps in our understanding the molecular, cellular and developmental mechanisms involved in the pathogenesis of hydrocephalus. Here, we demonstrate that specific deletion of RNA-binding protein (RBP) Hu antigen R (HuR) in the mouse brain results in hydrocephalus and causes postnatal death. HuR deficiency leads to impaired ependymal cell development with defective motile ciliogenesis in both female and male mice. Transcriptome-wide analysis reveals that HuR binds to mRNA transcripts related to ciliogenesis, including cilia and flagella associated protein 52 (Cfap52), the effector gene of Foxj-1 and Rfx transcriptional factors. HuR deficiency accelerates the degradation of Cfap52 mRNA, while overexpression of Cfap52 is able to promote the development of HuR-deficient ependymal cells. Taken together, our results unravel the important role of HuR in posttranscriptional regulation of ependymal cell development by stabilizing Cfap52 mRNA.SIGNIFICANCE STATEMENT This study identifies Hu antigen R (HuR) as a genetic factor involved in the pathogenesis of hydrocephalus. Mechanistically, HuR regulates ependymal cell differentiation and ciliogenesis through stabilizing Cfap52 mRNA, the effector gene of Foxj-1 and Rfx transcriptional factors.
Assuntos
Encéfalo/metabolismo , Proteína Semelhante a ELAV 1/metabolismo , Epêndima/metabolismo , Hidrocefalia/metabolismo , Animais , Cílios/metabolismo , Proteína Semelhante a ELAV 1/genética , Epêndima/citologia , Feminino , Regulação da Expressão Gênica , Hidrocefalia/genética , Masculino , Camundongos , Camundongos KnockoutRESUMO
Mutations in the Aminoadipate-Semialdehyde Synthase (AASS) gene encoding α-aminoadipic semialdehyde synthase lead to hyperlysinemia-I, a benign metabolic variant without clinical significance, and hyperlysinemia-II with developmental delay and intellectual disability. Although both forms of hyperlysinemia display biochemical phenotypes of questionable clinical significance, an association between neurologic disorder and a pronounced biochemical abnormality remains a challenging clinical question. Here, we report that Aass mutant male and female mice carrying the R65Q mutation in α-ketoglutarate reductase (LKR) domain have an elevated cerebral lysine level and a normal brain development, whereas the Aass mutant mice carrying the G489E mutation in saccharopine dehydrogenase (SDH) domain exhibit elevations of both cerebral lysine and saccharopine levels and a smaller brain with defective neuronal development. Mechanistically, the accumulated saccharopine, but not lysine, leads to impaired neuronal development by inhibiting the neurotrophic effect of glucose-6-phosphate isomerase (GPI). While extracellular supplementation of GPI restores defective neuronal development caused by G498E mutation in SDH of Aass. Altogether, our findings not only unravel the requirement for saccharopine degradation in neuronal development, but also provide the mechanistic insights for understanding the neurometabolic disorder of hyperlysinemia-II.SIGNIFICANCE STATEMENT The association between neurologic disorder and a pronounced biochemical abnormality in hyperlysinemia remains a challenging clinical question. Here, we report that mice carrying the R65Q mutation in lysine α-ketoglutarate reductase (LKR) domain of aminoadipate-semialdehyde synthase (AASS) have an elevated cerebral lysine levels and a normal brain development, whereas those carrying the G489E mutation in saccharopine dehydrogenase (SDH) domain of AASS exhibit an elevation of both cerebral lysine and saccharopine and a small brain with defective neuronal development. Furthermore, saccharopine impairs neuronal development by inhibiting the neurotrophic effect of glucose-6-phosphate isomerase (GPI). These findings demonstrate saccharopine degradation is essential for neuronal development.
Assuntos
Hiperlisinemias , Lisina , Animais , Feminino , Glucose-6-Fosfato Isomerase , Hiperlisinemias/genética , Hiperlisinemias/metabolismo , Lisina/análogos & derivados , Masculino , Camundongos , Sacaropina Desidrogenases/genética , Sacaropina Desidrogenases/metabolismoRESUMO
Neocortex development during embryonic stages requires the precise control of mRNA metabolism. Human antigen R (HuR) is a well-studied mRNA-binding protein that regulates mRNA metabolism, and it is highly expressed in the neocortex during developmental stages. Deletion of HuR does not impair neural progenitor cell proliferation or differentiation, but it disturbs the laminar structure of the neocortex. We report that HuR is expressed in postmitotic projection neurons during mouse brain development. Specifically, depletion of HuR in these neurons led to a mislocalization of CDP+ neurons in deeper layers of the cortex. Time-lapse microscopy showed that HuR was required for the promotion of cell motility in migrating neurons. PCR array identified profilin 1 (Pfn1) mRNA as a major binding partner of HuR in neurons. HuR positively mediated the stability of Pfn1 mRNA and influenced actin polymerization. Overexpression of Pfn1 successfully rescued the migration defects of HuR-deleted neurons. Our data reveal a post-transcriptional mechanism that maintains actin dynamics during neuronal migration.
Assuntos
Movimento Celular , Proteína Semelhante a ELAV 1/fisiologia , Neurônios/fisiologia , RNA Mensageiro/metabolismo , Animais , Padronização Corporal/genética , Movimento Celular/genética , Células Cultivadas , Embrião de Mamíferos , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células-Tronco Neurais/fisiologia , Neurogênese/genética , Gravidez , Profilinas/fisiologia , Processamento Pós-Transcricional do RNA/genéticaRESUMO
Adult neurogenesis is a multistage process during which newborn neurons are generated through the activation and proliferation of neural stem cells (NSCs) and integrated into existing neural networks. Impaired adult neurogenesis has been observed in various neurological and psychiatric disorders, suggesting its critical role in cognitive function, brain homeostasis, and neural repair. Over the past decades, mounting evidence has identified a strong association between metabolic status and adult neurogenesis. Here, we aim to summarize how amino acids and their neuroactive metabolites affect adult neurogenesis. Furthermore, we discuss the causal link between amino acid metabolism, adult neurogenesis, and neurological diseases. Finally, we propose that systematic elucidation of how amino acid metabolism regulates adult neurogenesis has profound implications not only for understanding the biological underpinnings of brain development and neurological diseases, but also for providing potential therapeutic strategies to intervene in disease progression.
Assuntos
Doenças do Sistema Nervoso , Células-Tronco Neurais , Humanos , Adulto , Recém-Nascido , Neurogênese/fisiologia , Neurônios/metabolismo , Células-Tronco Neurais/metabolismo , Encéfalo/metabolismo , Doenças do Sistema Nervoso/metabolismoRESUMO
Neural stem cells are multipotent stem cells that generate functional newborn neurons through a process called neurogenesis. Neurogenesis in the adult brain is tightly regulated and plays a pivotal role in the maintenance of brain function. Disruption of adult neurogenesis impairs cognitive function and is correlated with numerous neurologic disorders. Deciphering the mechanisms underlying adult neurogenesis not only advances our understanding of how the brain functions, but also offers new insight into neurologic diseases and potentially contributes to the development of effective treatments. The field of adult neurogenesis is experiencing significant growth in China. Chinese researchers have demonstrated a multitude of factors governing adult neurogenesis and revealed the underlying mechanisms of and correlations between adult neurogenesis and neurologic disorders. Here, we provide an overview of recent advancements in the field of adult neurogenesis due to Chinese scientists.
Assuntos
Doenças do Sistema Nervoso , Células-Tronco Neurais , Adulto , Recém-Nascido , Humanos , Neurogênese/fisiologia , Neurônios , China , HipocampoRESUMO
The establishment of axon/dendrite polarity is fundamental for neurons to integrate into functional circuits, and this process is critically dependent on microtubules (MTs). In the early stages of the establishment process, MTs in axons change dramatically with the morphological building of neurons; however, how the MT network changes are triggered is unclear. Here we show that CAMSAP1 plays a decisive role in the neuronal axon identification process by regulating the number of MTs. Neurons lacking CAMSAP1 form a multiple axon phenotype in vitro, while the multipolar-bipolar transition and radial migration are blocked in vivo. We demonstrate that the polarity regulator MARK2 kinase phosphorylates CAMSAP1 and affects its ability to bind to MTs, which in turn changes the protection of MT minus-ends and also triggers asymmetric distribution of MTs. Our results indicate that the polarized MT network in neurons is a decisive factor in establishing axon/dendritic polarity and is initially triggered by polarized signals.
Assuntos
Polaridade Celular/fisiologia , Proteínas Associadas aos Microtúbulos/metabolismo , Microtúbulos/fisiologia , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Imunoprecipitação , Camundongos , Proteínas Associadas aos Microtúbulos/genética , Neurônios , Paclitaxel , Ligação ProteicaRESUMO
Adult hippocampal neurogenesis, a process considered important for hippocampal function, is regulated at multiple molecular levels. Mutations in the gene encoding the WD40 repeat-containing protein WDR81 are associated with neurological disorders, including cerebellar ataxia, mental retardation, quadrupedal locomotion syndrome (CAMRQ2), and microcephaly. In this study, we show that ablation of WDR81 in adult neural progenitor cells (aNPCs) markedly reduced adult hippocampal neurogenesis and impaired hippocampus-dependent learning. WDR81 suppresses endosomal PtdIns3P synthesis, likely by inhibiting the assembly of the PI3K-III complex. In the absence of WDR81, endosomal PtdIns3P levels are greatly elevated, leading to endosomal persistence of the PtdIns3P-binding protein SARA and consequently hyperactivation of SARA-dependent TGFß signaling. Inhibition of PI3K-III activity or suppression of SARA-dependent TGFß signaling markedly ameliorated the defective adult neurogenesis in WDR81-deficient mice. Taken together, these findings not only uncover the requirement for the WDR81-SARA-TGFß axis in adult hippocampal neurogenesis, but also suggest that defective adult hippocampal neurogenesis contributes to the etiology of WDR81-related neurological diseases.
Assuntos
Proteínas de Ligação ao GTP , Proteínas do Tecido Nervoso/metabolismo , Células-Tronco Neurais , Neurogênese , Fator de Crescimento Transformador beta , Animais , Hipocampo/citologia , Hipocampo/metabolismo , Camundongos , Células-Tronco Neurais/metabolismoRESUMO
Dendritic spine development is crucial for the establishment of excitatory synaptic connectivity and functional neural circuits. Alterations in spine morphology and density have been associated with multiple neurological disorders. Autism candidate gene disconnected-interacting protein homolog 2 A (DIP2A) is known to be involved in acetylated coenzyme A (Ac-CoA) synthesis and is primarily expressed in the brain regions with abundant pyramidal neurons. However, the role of DIP2A in the brain remains largely unknown. In this study, we found that deletion of Dip2a in mice induced defects in spine morphogenesis along with thin postsynaptic density (PSD), and reduced synaptic transmission of pyramidal neurons. We further identified that DIP2A interacted with cortactin, an activity-dependent spine remodeling protein. The binding activity of DIP2A-PXXP motifs (P, proline; X, any residue) with the cortactin-Src homology 3 (SH3) domain was critical for maintaining the level of acetylated cortactin. Furthermore, Dip2a knockout (KO) mice exhibited autism-like behaviors, including excessive repetitive behaviors and defects in social novelty. Importantly, acetylation mimetic cortactin restored the impaired synaptic transmission and ameliorated repetitive behaviors in these mice. Altogether, our findings establish an initial link between DIP2A gene variations in autism spectrum disorder (ASD) and highlight the contribution of synaptic protein acetylation to synaptic processing.
Assuntos
Acetilcoenzima A/genética , Transtorno do Espectro Autista/genética , Cortactina/genética , Espinhas Dendríticas/metabolismo , Morfogênese/genética , Proteínas Nucleares/genética , Processamento de Proteína Pós-Traducional , Acetilcoenzima A/deficiência , Acetilação , Motivos de Aminoácidos , Animais , Animais Recém-Nascidos , Transtorno do Espectro Autista/metabolismo , Transtorno do Espectro Autista/fisiopatologia , Sítios de Ligação , Cortactina/metabolismo , Espinhas Dendríticas/ultraestrutura , Modelos Animais de Doenças , Embrião de Mamíferos , Regulação da Expressão Gênica no Desenvolvimento , Teste de Complementação Genética , Camundongos , Camundongos Knockout , Proteínas Nucleares/deficiência , Densidade Pós-Sináptica/metabolismo , Densidade Pós-Sináptica/ultraestrutura , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Células Piramidais/metabolismo , Células Piramidais/ultraestrutura , Transmissão SinápticaRESUMO
LncRNAs have recently emerged to influence the pathogenesis of fragile X syndrome (FXS), which is caused by the functional loss of fragile X mental retardation protein (FMRP). However, the interaction between FMRP and lncRNAs on regulating neuronal development remains elusive. Here, we reported that FMRP directly interacted with lncRNA TUG1, and decreased its stability. Furthermore, TUG1 bond to transcriptional regulator, SnoN, and negatively modulated SnoN-Ccd1 pathway to specifically control axonal development. These observations suggested interplay between FMRP and lncRNAs might contribute to the pathogenesis of FXS.
Assuntos
Proteína do X Frágil da Deficiência Intelectual/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Linhagem Celular , Células Cultivadas , Dactinomicina/farmacologia , Proteína do X Frágil da Deficiência Intelectual/genética , Hipocampo/metabolismo , Imuno-Histoquímica , Imunoprecipitação , Peptídeos e Proteínas de Sinalização Intracelular/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Proto-Oncogênicas/genética , Estabilidade de RNA/efeitos dos fármacos , RNA Longo não Codificante/genética , RNA Mensageiro/metabolismoRESUMO
Chronic stress has been observed to increase the risk of developing depression and induce neuronal alterations of synaptic plasticity, yet the underlying molecular mechanisms remain unclear. Here, we found that the ubiquitously expressed RNA-binding protein HuR was up-regulated in the medial prefrontal cortex (mPFC) of mice following chronic stress. In adult mice, AAV-Cre-mediated knockout of HuR in the mPFC prevented anxiety-like and depression-like behaviors induced by chronic stress. HuR was also required for the stress-induced dendritic spine loss and synaptic transmission deficits. Moreover, HuRflox/flox;Nex-Cre mice, which induce HuR loss of function from embryonic development, exhibited enhanced synaptic functions. Notably, we ascertained RhoA signaling to be regulated by HuR and involved in the modulation of structural synaptic plasticity in response to chronic stress. Our results demonstrate HuR is a critical modulator for the regulation of stress-induced synaptic plasticity alterations and depression, providing a potential therapeutic target for the treatment of depressive disorders.
Assuntos
Depressão/metabolismo , Proteína Semelhante a ELAV 1/metabolismo , Plasticidade Neuronal/fisiologia , Córtex Pré-Frontal/metabolismo , Animais , Depressão/etiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Restrição Física , Estresse Psicológico/complicaçõesRESUMO
Proper neuronal migration is critical for the formation of the six-layered neocortex in the mammalian brain. However, the precise control of neuronal migration is not well understood. Heterotrimeric guanine nucleotide binding proteins (G proteins), composed of Gα and Gßγ, transduce signals from G protein-coupled receptors to downstream effectors and play crucial roles in brain development. However, the functions of individual subunits of G proteins in prenatal brain development remain unclear. Here, we report that Gß2 is expressed in the embryonic neocortex, with abundant expression in the intermediate zone, and is significantly upregulated in differentiated neurons. Perturbation of Gß2 expression impairs the morphogenetic transformation of migrating neurons from multipolar to bipolar and subsequently delays neuronal migration. Moreover, Gß2 acts as a scaffold protein to organize the MP1-MEK1-ERK1/2 complex and mediates the phosphorylation of ERK1/2. Importantly, expression of a constitutively active variant of MEK1 rescues the migration defects that are caused by the loss of Gß2. In conclusion, our findings reveal that Gß2 regulates proper neuronal migration during neocortex development by activating the ERK1/2 signaling pathway.
Assuntos
Subunidades beta da Proteína de Ligação ao GTP/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Neocórtex/citologia , Neocórtex/embriologia , Neurônios/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Movimento Celular/genética , Polaridade Celular/fisiologia , Células Cultivadas , Feminino , Subunidades beta da Proteína de Ligação ao GTP/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Células HEK293 , Humanos , Sistema de Sinalização das MAP Quinases/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Nestina/metabolismo , Células-Tronco Neurais/fisiologia , Fosforilação/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismoRESUMO
The mammalian embryonic lethal abnormal vision (ELAV)-like protein HuD is a neuronal RNA-binding protein implicated in neuronal development, plasticity, and diseases. Although HuD has long been associated with neuronal development, the functions of HuD in neural stem cell differentiation and the underlying mechanisms have gone largely unexplored. Here we show that HuD promotes neuronal differentiation of neural stem/progenitor cells (NSCs) in the adult subventricular zone by stabilizing the mRNA of special adenine-thymine (AT)-rich DNA-binding protein 1 (SATB1), a critical transcriptional regulator in neurodevelopment. We find that SATB1 deficiency impairs the neuronal differentiation of NSCs, whereas SATB1 overexpression rescues the neuronal differentiation phenotypes resulting from HuD deficiency. Interestingly, we also discover that SATB1 is a transcriptional activator of HuD during NSC neuronal differentiation. In addition, we demonstrate that NeuroD1, a neuronal master regulator, is a direct downstream target of SATB1. Therefore, HuD and SATB1 form a positive regulatory loop that enhances NeuroD1 transcription and subsequent neuronal differentiation. Our results here reveal a novel positive feedback network between an RNA-binding protein and a transcription factor that plays critical regulatory roles in neurogenesis.
Assuntos
Proteína Semelhante a ELAV 4/metabolismo , Retroalimentação Fisiológica , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Neurogênese , Animais , Sequência de Bases , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Sítios de Ligação/genética , Western Blotting , Diferenciação Celular , Células Cultivadas , Proteína Semelhante a ELAV 4/genética , Ventrículos Laterais/citologia , Ventrículos Laterais/metabolismo , Masculino , Proteínas de Ligação à Região de Interação com a Matriz/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Confocal , Dados de Sequência Molecular , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Bulbo Olfatório/citologia , Bulbo Olfatório/metabolismo , Ligação Proteica , Interferência de RNA , Estabilidade de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
In both the embryonic and adult brain, a critical step in neurogenesis is neuronal maturation. Deficiency of MeCP2 leads to Rett syndrome, a severe neurodevelopmental disorder. We have previously shown that MeCP2 plays critical roles in the maturation step of new neurons during neurogenesis. MeCP2 is known to regulate the expression of brain-derived neurotrophic factor (BDNF), a potent neurotrophic factor for neuronal maturation. Nevertheless, how MeCP2 regulates BDNF expression and how MeCP2 deficiency leads to reduced BDNF expression remain unclear. Here, we show that MeCP2 regulates the expression of a microRNA, miR-15a. We find that miR-15a plays a significant role in the regulation of neuronal maturation. Overexpression of miR-15a inhibits dendritic morphogenesis in immature neurons. Conversely, a reduction in miR-15a has the opposite effect. We further show that miR-15a regulates expression levels of BDNF, and exogenous BDNF could partially rescue the neuronal maturation deficits resulting from miR-15a overexpression. Finally, inhibition of miR-15a could rescue neuronal maturation deficits in MeCP2-deficient adult-born new neurons. These results demonstrate a novel role for miR-15a in neuronal development and provide a missing link in the regulation of BDNF by MeCP2.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Dendritos/metabolismo , Proteína 2 de Ligação a Metil-CpG/deficiência , MicroRNAs/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Diferenciação Celular/genética , Regulação da Expressão Gênica , Hipocampo/patologia , Masculino , Proteína 2 de Ligação a Metil-CpG/metabolismo , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Modelos Biológicos , Mutação/genéticaRESUMO
Stabilized microtubules are required for neuronal morphogenesis and migration. However, the underlying mechanism is not fully understood. In this study, we demonstrate that myosin X (Myo10), which is composed of full-length myosin X (fMyo10) and headless myosin X (hMyo10), is important for axon development. fMyo10 is involved in axon elongation, whereas hMyo10 is critical for Tau-1 positive axon formation through stabilizing microtubules. Furthermore, in vivo studies reveal that hMyo10-mediated microtubule stability has a profound effect on both neuronal migration and dendritic arborization in the mammalian cerebral cortex. Taken together, our findings suggest that hMyo10 is involved in neuronal development both in vitro and in vivo by regulating microtubule stability.
Assuntos
Microtúbulos/fisiologia , Miosinas/fisiologia , Neurônios/fisiologia , Animais , Axônios/fisiologia , Movimento Celular/fisiologia , Células Cultivadas , Dendritos/fisiologia , Eletroporação , Feminino , Camundongos , Neurogênese/genética , Gravidez , TransfecçãoRESUMO
Fragile X syndrome (FXS), a common inherited form of intellectual disability with learning deficits, results from a loss of fragile X mental retardation protein (FMRP). Despite extensive research, treatment options for FXS remain limited. Since FMRP is known to play an important role in adult hippocampal neurogenesis and hippocampus-dependent learning and FMRP regulates the adult neural stem cell fate through the translational regulation of glycogen synthase kinase 3ß (GSK3ß), we investigated the effects of a GSK3ß inhibitor, SB216763, on Fmr1 knockout mice (Fmr1 KO). We found that the inhibition of GSK3ß could reverse the hippocampus-dependent learning deficits and rescue adult hippocampal neurogenesis at multiple stages in Fmr1 KO mice. Our results point to GSK3ß inhibition as a potential treatment for the learning deficits seen in FXS.
Assuntos
Síndrome do Cromossomo X Frágil/enzimologia , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Hipocampo/efeitos dos fármacos , Indóis/farmacologia , Aprendizagem/efeitos dos fármacos , Maleimidas/farmacologia , Neurogênese/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Animais , Modelos Animais de Doenças , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/patologia , Síndrome do Cromossomo X Frágil/fisiopatologia , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Hipocampo/fisiopatologia , Masculino , Camundongos , Camundongos Knockout , Rede Nervosa , Neurônios/efeitos dos fármacos , Neurônios/ultraestrutura , Fosforilação/efeitos dos fármacosRESUMO
Despite seizure control by early high-dose pyridoxine (vitamin B6) treatment, at least 75% of pyridoxine-dependent epilepsy (PDE) patients with ALDH7A1 mutation still suffer from intellectual disability. It points to a need for additional therapeutic interventions for PDE beyond pyridoxine treatment, which provokes us to investigate the mechanisms underlying the impairment of brain hemostasis by ALDH7A1 deficiency. In this study, we show that ALDH7A1-deficient mice with seizure control exhibit altered adult hippocampal neurogenesis and impaired cognitive functions. Mechanistically, ALDH7A1 deficiency leads to the accumulation of toxic lysine catabolism intermediates, α-aminoadipic-δ-semialdehyde and its cyclic form, δ-1-piperideine-6-carboxylate, which in turn impair de novo pyrimidine biosynthesis and inhibit NSC proliferation and differentiation. Notably, supplementation of pyrimidines rescues abnormal neurogenesis and cognitive impairment in ALDH7A1-deficient adult mice. Therefore, our findings not only define the important role of ALDH7A1 in the regulation of adult hippocampal neurogenesis but also provide a potential therapeutic intervention to ameliorate the defective mental capacities in PDE patients with seizure control.
Assuntos
Ácido 2-Aminoadípico/análogos & derivados , Aldeído Desidrogenase , Epilepsia , Piridoxina , Humanos , Animais , Camundongos , Piridoxina/farmacologia , Convulsões/tratamento farmacológico , Convulsões/etiologia , Pirimidinas/farmacologia , CogniçãoRESUMO
Fragile X syndrome (FXS), the most common form of inherited mental retardation, is caused by the loss of functional fragile X mental retardation protein (FMRP). FMRP is an RNA-binding protein that can regulate the translation of specific mRNAs. Adult neurogenesis, a process considered important for neuroplasticity and memory, is regulated at multiple molecular levels. In this study, we investigated whether Fmrp deficiency affects adult neurogenesis. We show that in a mouse model of fragile X syndrome, adult neurogenesis is indeed altered. The loss of Fmrp increases the proliferation and alters the fate specification of adult neural progenitor/stem cells (aNPCs). We demonstrate that Fmrp regulates the protein expression of several components critical for aNPC function, including CDK4 and GSK3beta. Dysregulation of GSK3beta led to reduced Wnt signaling pathway activity, which altered the expression of neurogenin1 and the fate specification of aNPCs. These data unveil a novel regulatory role for Fmrp and translational regulation in adult neurogenesis.