RESUMEN
Advanced paternal age can have deleterious effects on various traits in the next generation. Here, we establish a paternal-aging model in mice to understand the molecular mechanisms of transgenerational epigenetics. Whole-genome target DNA methylome analyses of sperm from aged mice reveal more hypo-methylated genomic regions enriched in REST/NRSF binding motifs. Gene set enrichment analyses also reveal the upregulation of REST/NRSF target genes in the forebrain of embryos from aged fathers. Offspring derived from young mice administrated with a DNA de-methylation drug phenocopy the abnormal vocal communication of pups derived from aged fathers. In conclusion, hypo-methylation of sperm DNA can be a key molecular feature modulating neurodevelopmental programs in offspring by causing fluctuations in the expression of REST/NRSF target genes.
Asunto(s)
Metilación de ADN , Edad Paterna , Animales , Epigénesis Genética , Padre , Humanos , Masculino , Ratones , Espermatozoides/metabolismoRESUMEN
BACKGROUND: Repressor element 1-silencing transcription factor (REST) is a master regulator that is highly expressed in multipotent stem cells to repress gene networks involving a wide range of biological processes. A recent study has suggested that REST might be involved in a misregulation of its target genes in the embryonic brain of offspring derived from aged fathers. However, detailed analyses of the REST function in spermatogenesis are lacking due to difficulty in the detection of REST protein in specific cell types. RESULTS: To determine localization of REST, we generated an epitope tag knock-in (KI) mouse line with the C-terminus insertion of a podoplanin (PA)-tag at an endogenous Rest locus by the CRISPR/Cas9 system. Localization of the PA-tag was confirmed in neural stem cells marked with Pax6 in the embryonic brain. Moreover, PA-tagged REST was detected in undifferentiated and differentiating spermatogonia as well as Sertoli cells in both neonatal and adult testes. CONCLUSIONS: We demonstrate that REST is expressed at the early step of spermatogenesis and suggest a possibility that REST may modulate the epigenetic state of male germline cells. Our KI mice may be useful for studying REST-associated molecular mechanisms of neurodevelopmental and age-related disorders.
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Edición Génica , Testículo , Animales , Epítopos/genética , Epítopos/metabolismo , Masculino , Ratones , Proteínas Represoras , Espermatogénesis/genética , Espermatogonias/metabolismo , Testículo/metabolismo , Factores de Transcripción/metabolismoRESUMEN
The subcommissural organ (SCO) is a part of the circumventricular organs located in the dorsocaudal region of the third ventricle at the entrance of the aqueduct of Sylvius. The SCO comprises epithelial cells and produces high molecular weight glycoproteins, which are secreted into the third ventricle and become part of Reissner's fibre in the cerebrospinal fluid. Abnormal development of the SCO has been linked with congenital hydrocephalus, a condition characterized by excessive accumulation of cerebrospinal fluid in the brain. In the present study, we characterized the SCO cells in the adult mouse brain to gain insights into the possible role of this brain region. Immunohistochemical analyses revealed that expression of Pax6, a transcription factor essential for SCO differentiation during embryogenesis, is maintained in the SCO at postnatal stages from P0 to P84. SCO cells in the adult brain expressed known neural stem/progenitor cell (NSPC) markers, Sox2 and vimentin. The adult SCO cells also expressed proliferating marker PCNA, although expression of another proliferation marker Ki67, indicating a G2 /M phase, was not detected. The SCO cells did not incorporate BrdU, a marker for DNA synthesis in the S phase. Therefore, the SCO cells have a potential for proliferation but are quiescent for cell division in the adult. The SCO cells also expressed GFAP, a marker for astrocytes or NSPCs, but not NeuN (for neurons). A few cells positive for Iba1 (microglia), Olig2 (for oligodendrocytes) and PDGFRα (oligodendrocyte progenitors) existed within or on the periphery of the SCO. These findings revealed that the SCO cells have a unique feature as secretory yet immature neuroepithelial cells in the adult mouse brain.
Asunto(s)
Hidrocefalia , Órgano Subcomisural , Animales , Ventrículos Cerebrales/metabolismo , Glicoproteínas/metabolismo , Hidrocefalia/líquido cefalorraquídeo , Hidrocefalia/genética , Ratones , Células NeuroepitelialesRESUMEN
Pax6 is a sequence-specific DNA binding transcription factor that positively and negatively regulates transcription and is expressed in multiple cell types in the developing and adult central nervous system (CNS). As indicated by the morphological and functional abnormalities in spontaneous Pax6 mutant rodents, Pax6 plays pivotal roles in various biological processes in the CNS. At the initial stage of CNS development, Pax6 is responsible for brain patterning along the anteroposterior and dorsoventral axes of the telencephalon. Regarding the anteroposterior axis, Pax6 is expressed inversely to Emx2 and Coup-TF1, and Pax6 mutant mice exhibit a rostral shift, resulting in an alteration of the size of certain cortical areas. Pax6 and its downstream genes play important roles in balancing the proliferation and differentiation of neural stem cells. The Pax6 gene was originally identified in mice and humans 30 years ago via genetic analyses of the eye phenotypes. The human PAX6 gene was discovered in patients who suffer from WAGR syndrome (i.e., Wilms tumor, aniridia, genital ridge defects, mental retardation). Mutations of the human PAX6 gene have also been reported to be associated with autism spectrum disorder (ASD) and intellectual disability. Rodents that lack the Pax6 gene exhibit diverse neural phenotypes, which might lead to a better understanding of human pathology and neurodevelopmental disorders. This review describes the expression and function of Pax6 during brain development, and their implications for neuropathology.
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Trastorno del Espectro Autista , Discapacidad Intelectual , Trastornos del Neurodesarrollo , Animales , Proteínas del Ojo/genética , Proteínas del Ojo/metabolismo , Proteínas de Homeodominio/genética , Humanos , Ratones , Trastornos del Neurodesarrollo/genética , Factor de Transcripción PAX6/genética , Factor de Transcripción PAX6/metabolismo , Factores de Transcripción Paired Box/genética , Factores de Transcripción Paired Box/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Telencéfalo/metabolismoRESUMEN
The evolution of unique organ structures is associated with changes in conserved developmental programs. However, characterizing the functional conservation and variation of homologous transcription factors (TFs) that dictate species-specific cellular dynamics has remained elusive. Here, we dissect shared and divergent functions of Pax6 during amniote brain development. Comparative functional analyses revealed that the neurogenic function of Pax6 is highly conserved in the developing mouse and chick pallium, whereas stage-specific binary functions of Pax6 in neurogenesis are unique to mouse neuronal progenitors, consistent with Pax6-dependent temporal regulation of Notch signaling. Furthermore, we identified that Pax6-dependent enhancer activity of Dbx1 is extensively conserved between mammals and chick, although Dbx1 expression in the developing pallium is highly divergent in these species. Our results suggest that spatiotemporal changes in Pax6-dependent regulatory programs contributed to species-specific neurogenic patterns in mammalian and avian lineages, which underlie the morphological divergence of the amniote pallial architectures.
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Proteínas Aviares/fisiología , Encéfalo/embriología , Encéfalo/fisiología , Factor de Transcripción PAX6/fisiología , Animales , Animales Modificados Genéticamente , Proteínas Aviares/genética , Embrión de Pollo , Elementos de Facilitación Genéticos , Evolución Molecular , Femenino , Eliminación de Gen , Regulación del Desarrollo de la Expresión Génica , Proteínas de Homeodominio/genética , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Ratones Noqueados , Ratones Transgénicos , Neurogénesis/genética , Neurogénesis/fisiología , Factor de Transcripción PAX6/deficiencia , Factor de Transcripción PAX6/genética , Embarazo , Receptores Notch/genética , Receptores Notch/fisiología , Transducción de Señal , Especificidad de la EspecieRESUMEN
Bisphenol A (BPA) is an environmental risk factor for autism spectrum disorder (ASD). BPA exposure dysregulates ASD-related genes in the hippocampus and neurological functions of offspring. However, whether prenatal BPA exposure has an impact on genes in the prefrontal cortex, another brain region highly implicated in ASD, and through what mechanisms have not been investigated. Here, we demonstrated that prenatal BPA exposure disrupts the transcriptome-interactome profiles of the prefrontal cortex of neonatal rats. Interestingly, the list of BPA-responsive genes was significantly enriched with known ASD candidate genes, as well as genes that were dysregulated in the postmortem brain tissues of ASD cases from multiple independent studies. Moreover, several differentially expressed genes in the offspring's prefrontal cortex were the targets of ASD-related transcription factors, including AR, ESR1, and RORA. The hypergeometric distribution analysis revealed that BPA may regulate the expression of such genes through these transcription factors in a sex-dependent manner. The molecular docking analysis of BPA and ASD-related transcription factors revealed novel potential targets of BPA, including RORA, SOX5, TCF4, and YY1. Our findings indicated that prenatal BPA exposure disrupts ASD-related genes in the offspring's prefrontal cortex and may increase the risk of ASD through sex-dependent molecular mechanisms, which should be investigated further.
Asunto(s)
Trastorno del Espectro Autista/genética , Compuestos de Bencidrilo/efectos adversos , Perfilación de la Expresión Génica/métodos , Fenoles/efectos adversos , Corteza Prefrontal/química , Efectos Tardíos de la Exposición Prenatal/genética , Factores de Transcripción/genética , Animales , Trastorno del Espectro Autista/inducido químicamente , Modelos Animales de Enfermedad , Receptor alfa de Estrógeno/genética , Femenino , Regulación de la Expresión Génica , Simulación del Acoplamiento Molecular , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Ratas , Receptores Androgénicos/genética , Análisis de Secuencia de ARN , Caracteres SexualesRESUMEN
BACKGROUND: During development, Cajal-Retzius (CR) cells are the first generated and essential pioneering neurons that control neuronal migration and arealization in the mammalian cortex. CR cells are derived from specific regions within the telencephalon, that is, the pallial septum in the rostromedial cortex, the pallial-subpallial boundary, and the cortical hem (CH) in the caudomedial cortex. However, the molecular mechanism underlying the generation of CR cell subtypes in distinct regions of origin is poorly understood. RESULTS: We found that double-sex and mab-3 related transcription factor (Dmrt) genes, that is, Dmrta1 and Dmrt3, were expressed in the progenitor domains that produce CR cells. The number of CH-derived CR cells was severely decreased in Dmrt3 mutants, especially in Dmrta1 and Dmrt3 double mutants. The reduced production of the CR cells was consistent with the developmental impairment of the CH structures in the medial telencephalon from which the CR cells are produced. CONCLUSION: Dmrta1 and Dmrt3 cooperatively regulate patterning of the CH structure and production of the CR cells from the CH during cortical development.
Asunto(s)
Neuronas/metabolismo , Telencéfalo/citología , Factores de Transcripción/metabolismo , Animales , Linaje de la Célula , Movimiento Celular/fisiología , Neurogénesis/fisiología , Factores de Transcripción/genéticaRESUMEN
The anterior pituitary originates from the adenohypophyseal placode. Both the preplacode region and neural crest (NC) derive from subdivision of the neural border region, and further individualization of the placode domain is established by a reciprocal interaction between placodal precursors and NC cells (NCCs). It has long been known that NCCs are present in the adenohypophysis as interstitial cells. A recent report demonstrated that NCCs also contribute to the formation of pericytes in the developing pituitary. Here, we attempt to further clarify the role of NCCs in pituitary development using P0-Cre/EGFP reporter mice. Spatiotemporal analyses revealed that GFP-positive NCCs invaded the adenohypophysis in a stepwise manner. The first wave was detected on mouse embryonic day 9.5 (E9.5), when the pituitary primordium begins to be formed by adenohypophyseal placode cells; the second wave occurred on E14.5, when vasculogenesis proceeds from Atwell's recess. Finally, fate tracing of NCCs demonstrated that NC-derived cells in the adenohypophysis terminally differentiate into all hormone-producing cell lineages as well as pericytes. Our data suggest that NCCs contribute to pituitary organogenesis and vasculogenesis in conjunction with placode-derived pituitary stem/progenitor cells.
Asunto(s)
Cresta Neural/crecimiento & desarrollo , Organogénesis/fisiología , Hipófisis/embriología , Animales , Embrión de Mamíferos , Inmunohistoquímica , Ratones , Ratones Transgénicos , Modelos AnimalesRESUMEN
The anterior part of the embryonic telencephalon gives rise to several brain regions that are important for animal behavior, including the frontal cortex (FC) and the olfactory bulb. The FC plays an important role in decision-making behaviors, such as social and cognitive behavior, and the olfactory bulb is involved in olfaction. Here, we show the organizing activity of fibroblast growth factor 8 (Fgf8) in the regionalization of the anterior telencephalon, specifically the FC and the olfactory bulb. Misexpression of Fgf8 in the most anterior part of the mouse telencephalon at embryonic day 11.5 (E11.5) by ex utero electroporation resulted in a lateral shift of dorsal FC subdivision markers and a lateral expansion of the dorsomedial part of the FC, the future anterior cingulate and prelimbic cortex. Fgf8-transfected brains had lacked ventral FC, including the future orbital cortex, which was replaced by the expanded olfactory bulb. The olfactory region occupied a larger area of the FC when transfection efficiency of Fgf8 was higher. These results suggest that Fgf8 regulates the proportions of the FC and olfactory bulb in the anterior telencephalon and has a medializing effect on the formation of FC subdivisions.
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Factor 8 de Crecimiento de Fibroblastos/metabolismo , Telencéfalo/metabolismo , Animales , Corteza Cerebral/embriología , Corteza Cerebral/metabolismo , Factor 8 de Crecimiento de Fibroblastos/genética , Factores de Crecimiento de Fibroblastos/metabolismo , Regulación del Desarrollo de la Expresión Génica , Ratones , Bulbo Olfatorio/embriología , Bulbo Olfatorio/metabolismo , Telencéfalo/embriologíaRESUMEN
Omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFAs) are essential nutrients. Although several studies have suggested that a balanced dietary n-6:n-3 ratio is essential for brain development, the underlying cellular and molecular mechanism is poorly understood. Here, we found that feeding pregnant mice an n-6 excess/n-3 deficient diet, which reflects modern human diets, impairsed neocortical neurogenesis in the offspring. This impaired neurodevelopment occurs through a precocious fate transition of neural stem cells from the neurogenic to gliogenic lineage. A comprehensive mediator lipidomics screen revealed key mediators, epoxy metabolites, which were confirmed functionally using a neurosphere assay. Importantly, although the offspring were raised on a well-balanced n-6:n-3 diet, they exhibited increased anxiety-related behavior in adulthood. These findings provide compelling evidence that excess maternal consumption of n-6 PUFAs combined with insufficient intake of n-3 PUFAs causes abnormal brain development that can have long-lasting effects on the offspring's mental state.
Asunto(s)
Ácidos Grasos Omega-3 , Ácidos Grasos Omega-6/deficiencia , Exposición Materna/efectos adversos , Neocórtex/crecimiento & desarrollo , Células-Madre Neurales/metabolismo , Neurogénesis , Animales , Ácidos Grasos Omega-6/metabolismo , Femenino , Ratones , Neocórtex/patología , Células-Madre Neurales/patología , EmbarazoRESUMEN
The transcription factor Pax6 balances cell proliferation and neuronal differentiation in the mammalian developing neocortex by regulating the expression of target genes. Using microarray analysis, we observed the down-regulation of Dmrta1 (doublesex and mab-3-related transcription factor-like family A1) in the telencephalon of Pax6 homozygous mutant rats (rSey(2) /rSey(2) ). Dmrta1 expression was restricted to the neural stem/progenitor cells of the dorsal telencephalon. Overexpression of Dmrta1 induced the expression of the proneural gene Neurogenin2 (Neurog2) and conversely repressed Ascl1 (Mash1), a proneural gene expressed in the ventral telencephalon. We found that another Dmrt family molecule, Dmrt3, induced Neurog2 expression in the dorsal telencephalon. Our novel findings suggest that dual regulation of proneural genes mediated by Pax6 and Dmrt family members is crucial for cortical neurogenesis.
Asunto(s)
Proteínas del Ojo/genética , Regulación del Desarrollo de la Expresión Génica , Proteínas de Homeodominio/genética , Neurogénesis/genética , Factores de Transcripción Paired Box/genética , Proteínas Represoras/genética , Telencéfalo/metabolismo , Factores de Transcripción/metabolismo , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Células Cultivadas , Embrión de Mamíferos , Proteínas del Ojo/metabolismo , Femenino , Proteínas de Homeodominio/metabolismo , Masculino , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Células-Madre Neurales/metabolismo , Células-Madre Neurales/fisiología , Factor de Transcripción PAX6 , Factores de Transcripción Paired Box/metabolismo , Embarazo , Ratas , Ratas Sprague-Dawley , Proteínas Represoras/metabolismo , Telencéfalo/embriología , Factores de Transcripción/genéticaRESUMEN
Asymmetric cell division and cell cycle regulation are fundamental mechanisms of mammalian brain development and evolution. Cyclin D2, a positive regulator of G1 progression, shows a unique localization within radial glial (RG) cells (i.e., the neural progenitor in the developing neocortex). Cyclin D2 accumulates at the very basal tip of the RG cell (i.e., the basal endfoot) via a unique cis-regulatory sequence found in the 3' untranslated region (3'UTR) of its mRNA. During RG division, Cyclin D2 protein is asymmetrically distributed to two daughter cells following mitosis. The daughter cell that inherits Cyclin D2 mRNA maintains its self-renewal capability, while its sibling undergoes differentiation. A similar localization pattern of Cyclin D2 protein has been observed in the human fetal cortical primordium, suggesting a common mechanism of maintenance of neural progenitors that may be evolutionarily conserved across higher mammals such as primates. Here, we discuss our findings and the Cyclin D2 function in mammalian brain development and evolution.
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Encéfalo/embriología , Ciclina D2/metabolismo , Mamíferos/genética , Células-Madre Neurales/metabolismo , Animales , Encéfalo/citología , Encéfalo/metabolismo , Proliferación Celular , Ciclina D2/genética , Humanos , Mamíferos/metabolismoRESUMEN
Sex bias is known in the prevalence/pathology of neurodevelopmental disorders. Sex-dependent differences of the certain brain areas are known to emerge perinatally through the exposure to sex hormones, while gene expression patterns in the rodent embryonic brain does not seem to be completely the same between male and female. To investigate potential sex differences in gene expression and cortical organization during the embryonic period in mice, we conducted a comprehensive analysis of gene expression for the telencephalon at embryonic day (E) 11.5 (a peak of neural stem cell expansion) and E14.5 (a peak of neurogenesis) using bulk RNA-seq data. As a result, our data showed the existence of notable sex differences in gene expression patterns not obviously at E11.5, but clearly at E14.5 when neurogenesis has become its peak. These data can be useful for exploring potential contribution of genes exhibiting sex differences to the divergence in brain development. Additionally, our data underscore the significance of studying the embryonic period to gain a deeper understanding of sex differences in brain development.
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Telencéfalo , Transcriptoma , Animales , Telencéfalo/embriología , Telencéfalo/metabolismo , Ratones , Femenino , Masculino , Neurogénesis/genética , Caracteres SexualesRESUMEN
BACKGROUND: Recent studies have shown that prenatal BPA exposure altered the transcriptome profiles of autism-related genes in the offspring's hippocampus, disrupting hippocampal neuritogenesis and causing male-specific deficits in learning. However, the sex differences in the effects of prenatal BPA exposure on the developing prefrontal cortex, which is another brain region highly implicated in autism spectrum disorder (ASD), have not been investigated. METHODS: We obtained transcriptome data from RNA sequencing analysis of the prefrontal cortex of male and female rat pups prenatally exposed to BPA or control and reanalyzed. BPA-responsive genes associated with cortical development and social behaviors were selected for confirmation by qRT-PCR analysis. Neuritogenesis of primary cells from the prefrontal cortex of pups prenatally exposed to BPA or control was examined. The social behaviors of the pups were assessed using the two-trial and three-chamber tests. The male-specific impact of the downregulation of a selected BPA-responsive gene (i.e., Sema5a) on cortical development in vivo was interrogated using siRNA-mediated knockdown by an in utero electroporation technique. RESULTS: Genes disrupted by prenatal BPA exposure were associated with ASD and showed sex-specific dysregulation. Sema5a and Slc9a9, which were involved in neuritogenesis and social behaviors, were downregulated only in males, while Anxa2 and Junb, which were also linked to neuritogenesis and social behaviors, were suppressed only in females. Neuritogenesis was increased in males and showed a strong inverse correlation with Sema5a and Slc9a9 expression levels, whereas, in the females, neuritogenesis was decreased and correlated with Anxa2 and Junb levels. The siRNA-mediated knockdown of Sema5a in males also impaired cortical development in utero. Consistent with Anxa2 and Junb downregulations, deficits in social novelty were observed only in female offspring but not in males. CONCLUSION: This is the first study to show that prenatal BPA exposure dysregulated the expression of ASD-related genes and functions, including cortical neuritogenesis and development and social behaviors, in a sex-dependent manner. Our findings suggest that, besides the hippocampus, BPA could also exert its adverse effects through sex-specific molecular mechanisms in the offspring's prefrontal cortex, which in turn would lead to sex differences in ASD-related neuropathology and clinical manifestations, which deserves further investigation.
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Compuestos de Bencidrilo , Fenoles , Corteza Prefrontal , Efectos Tardíos de la Exposición Prenatal , Caracteres Sexuales , Conducta Social , Animales , Femenino , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Fenoles/toxicidad , Fenoles/efectos adversos , Masculino , Compuestos de Bencidrilo/toxicidad , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Trastorno Autístico/genética , Trastorno Autístico/inducido químicamente , Ratas Sprague-Dawley , Ratas , Trastorno del Espectro Autista/inducido químicamente , Trastorno del Espectro Autista/genéticaRESUMEN
Paternal aging has consistently been linked to an increased risk of neurodevelopmental disorders, including autism spectrum disorder (ASD), in offspring. Recent evidence has highlighted the involvement of epigenetic factors. In this study, we aimed to investigate age-related alterations in microRNA (miRNA) profiles of mouse sperm and analyze target genes regulated by differentially expressed miRNAs (DEmiRNAs). Microarray analyses were conducted on sperm samples from mice at different ages: 3 months (3 M), over 12 M, and beyond 20 M. We identified 26 miRNAs with differential expression between the 3 and 20 M mice, 34 miRNAs between the 12 and 20 M mice, and 2 miRNAs between the 3 and 12 M mice. The target genes regulated by these miRNAs were significantly associated with apoptosis/ferroptosis pathways and the nervous system. We revealed alterations in sperm miRNA profiles due to aging and suggest that the target genes regulated by these DEmiRNAs are associated with apoptosis and the nervous system, implying a potential link between paternal aging and an increased risk of neurodevelopmental disorders such as ASD. The observed age-related changes in sperm miRNA profiles have the potential to impact sperm quality and subsequently affect offspring development.
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Trastorno del Espectro Autista , MicroARNs , Masculino , Ratones , Animales , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/metabolismo , Semen/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Espermatozoides/metabolismo , Envejecimiento/genéticaRESUMEN
A small number of offspring are born from the numerous sperm generated from spermatogonial stem cells (SSCs). However, little is known regarding the rules and molecular mechanisms that govern germline transmission patterns. Here we report that the Trp53 tumor suppressor gene limits germline genetic diversity via Cdkn1a. Trp53-deficient SSCs outcompeted wild-type (WT) SSCs and produced significantly more progeny after co-transplantation into infertile mice. Lentivirus-mediated transgenerational lineage analysis showed that offspring bearing the same virus integration were repeatedly born in a non-random pattern from WT SSCs. However, SSCs lacking Trp53 or Cdkn1a sired transgenic offspring in random patterns with increased genetic diversity. Apoptosis of KIT+ differentiating germ cells was reduced in Trp53- or Cdkn1a-deficient mice. Reduced CDKN1A expression in Trp53-deficient spermatogonia suggested that Cdkn1a limits genetic diversity by supporting apoptosis of syncytial spermatogonial clones. Therefore, the TRP53-CDKN1A pathway regulates tumorigenesis and the germline transmission pattern.
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Células Madre Germinales Adultas , Semen , Animales , Apoptosis/genética , Masculino , Ratones , Espermatogénesis/genética , Espermatogonias/metabolismo , EspermatozoidesRESUMEN
CHAMP1 is a gene associated with intellectual disability, which was originally identified as being involved in the maintenance of kinetochore-microtubule attachment. To explore the neuronal defects caused by CHAMP1 deficiency, we established mice that lack CHAMP1. Mice that are homozygous knockout for CHAMP1 were slightly smaller than wild-type mice and died soon after birth on pure C57BL/6J background. Although gross anatomical defects were not found in CHAMP1 -/- mouse brains, mitotic cells were increased in the cerebral cortex. Neuronal differentiation was delayed in CHAMP1 -/- neural stem cells in vitro, which was also suggested in vivo by CHAMP1 knockdown. In a behavioural test battery, adult CHAMP1 heterozygous knockout mice showed mild memory defects, altered social interaction, and depression-like behaviours. In transcriptomic analysis, genes related to neurotransmitter transport and neurodevelopmental disorder were downregulated in embryonic CHAMP1 -/- brains. These results suggest that CHAMP1 plays a role in neuronal development, and CHAMP1-deficient mice resemble some aspects of individuals with CHAMP1 mutations.
RESUMEN
The Dmrt genes encode the transcription factor containing the DM (doublesex and mab-3) domain, an intertwined zinc finger-like DNA binding module. While Dmrt genes are mainly involved in the sexual development of various species, recent studies have revealed that Dmrt genes, which belong to the DmrtA subfamily, are differentially expressed in the embryonic brain and spinal cord and are essential for the development of the central nervous system. Herein, we summarize recent studies that reveal the multiple functions of the Dmrt genes in various aspects of vertebrate neural development, including brain patterning, neurogenesis, and the specification of neurons.
RESUMEN
Our recent study has shown that prenatal exposure to bisphenol A (BPA) altered the expression of genes associated with autism spectrum disorder (ASD). In this study, we further investigated the effects of prenatal BPA exposure on ASD-related genes known to regulate neuronal viability, neuritogenesis, and learning/memory, and assessed these functions in the offspring of exposed pregnant rats. We found that prenatal BPA exposure increased neurite length, the number of primary neurites, and the number of neurite branches, but reduced the size of the hippocampal cell body in both sexes of the offspring. However, in utero exposure to BPA decreased the neuronal viability and the neuronal density in the hippocampus and impaired learning/memory only in the male offspring while the females were not affected. Interestingly, the expression of several ASD-related genes (e.g. Mief2, Eif3h, Cux1, and Atp8a1) in the hippocampus were dysregulated and showed a sex-specific correlation with neuronal viability, neuritogenesis, and/or learning/memory. The findings from this study suggest that prenatal BPA exposure disrupts ASD-related genes involved in neuronal viability, neuritogenesis, and learning/memory in a sex-dependent manner, and these genes may play an important role in the risk and the higher prevalence of ASD in males subjected to prenatal BPA exposure.
Asunto(s)
Trastorno del Espectro Autista/metabolismo , Compuestos de Bencidrilo/toxicidad , Regulación de la Expresión Génica/efectos de los fármacos , Hipocampo/metabolismo , Fenoles/toxicidad , Efectos Tardíos de la Exposición Prenatal/metabolismo , Caracteres Sexuales , Animales , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/patología , Femenino , Hipocampo/patología , Masculino , Embarazo , Efectos Tardíos de la Exposición Prenatal/genética , Efectos Tardíos de la Exposición Prenatal/patología , Ratas , Ratas WistarRESUMEN
Histamine acts as a neurotransmitter to regulate various physiological processes. Brain histamine is synthesized from an essential amino acid histidine in a reaction catalysed by histidine decarboxylase (Hdc). Hdc-positive neurons exist mainly in the tuberomammillary nucleus (TMN) of the posterior hypothalamus and project their axons to the entire brain. Recent studies have reported that a chronic decrease in histamine levels in the adult human brain was observed in several neurological disorders. However, it is poorly understood whether lower histamine levels play a causative role in those disorders. In the present study, we induced chronic histamine deficiency in the brains of adult mice to allow direct interpretation of the relationship between an impaired histaminergic nervous system and the resultant phenotype. To induce chronic brain histamine deficiency starting in adulthood, adeno-associated virus expressing Cre recombinase was microinjected into the TMN of Hdc flox mice (cKO mice) at the age of 8 weeks. Immunohistochemical analysis showed expression of Cre recombinase in the TMN of cKO mice. The reduction of histamine contents with the decreased Hdc expression in cKO brain was also confirmed. Behavioural studies revealed that chronic histamine depletion in cKO mice induced depression-like behaviour, decreased locomotor activity in the home cage, and impaired aversive memory. Sleep analysis showed that cKO mice exhibited a decrease in wakefulness and increase in non-rapid eye movement sleep throughout the day. Taken together, this study clearly demonstrates that chronic histamine depletion in the adult mouse brain plays a causative role in brain dysfunction.