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1.
Eur J Histochem ; 68(2)2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38766720

RESUMO

Previous studies on the granular layer of the cerebellar cortex have revealed a wide distribution of different subpopulations of less-known large neuron types, called "non-traditional large neurons", which are distributed in three different zones of the granular layer. These neuron types are mainly involved in the formation of intrinsiccircuits inside the cerebellar cortex. A subpopulation of these neuron types is represented by the synarmotic neuron, which could play a projective role within the cerebellar circuitry. The synarmotic neuron cell body map within the internal zone of the granular layer or in the subjacent white substance. Furthermore, the axon crosses the granular layer and runs in the subcortical white substance, to reenter in an adjacent granular layer, associating two cortico-cerebellar regions of the same folium or of different folia, or could project to the intrinsic cerebellar nuclei. Therefore, along with the Purkinje neuron, the traditional projective neuron type of the cerebellar cortex, the synarmotic neuron is candidate to represent the second projective neuron type of the cerebellar cortex. Studies of chemical neuroanatomy evidenced a predominant inhibitory GABAergic nature of the synarmotic neuron, suggesting that it may mediate an inhibitory GABAergic output of cerebellar cortex within cortico-cortical interconnections or in projections towards intrinsic cerebellar nuclei. On this basis, the present minireview mainly focuses on the morphofunctional and neurochemical data of the synarmotic neuron, and explores its potential involvement in some forms of cerebellar ataxias.


Assuntos
Córtex Cerebelar , Neurônios , Córtex Cerebelar/citologia , Animais , Humanos , Neurônios/citologia , Neurônios/metabolismo , Neurônios GABAérgicos/metabolismo , Neurônios GABAérgicos/citologia
2.
Eur J Transl Myol ; 33(3)2023 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-37522802

RESUMO

The autophagy process recycles dysfunctional cellular components and protein aggregates by sequestering them in autophagosomes directed to lysosomes for enzymatic degradation. A basal level of autophagy is essential for skeletal muscle maintenance. Increased autophagy occurs in several forms of muscular dystrophy and in the merosin-deficient congenital muscular dystrophy 1A mouse model (dy3k/dy3k) lacking the laminin-α2 chain. This pilot study aimed to compare autophagy marker expression and autophagosomes presence using light and electron microscopes and western blotting in diagnostic muscle biopsies from newborns affected by different congenital muscular myopathies and dystrophies. Morphological examination showed dystrophic muscle features, predominance of type 2A myofibers, accumulation of autophagosomes in the subsarcolemmal areas, increased number of autophagosomes overexpressing LC3b, Beclin-1 and ATG5, in the merosin-deficient newborn suggesting an increased autophagy. In Duchenne muscular dystrophy, nemaline myopathy, and spinal muscular atrophy the predominant accumulation of p62+ puncta rather suggests an autophagy impairment.

3.
Artigo em Inglês | MEDLINE | ID: mdl-36515028

RESUMO

BACKGROUND: Neurodegenerative disorders may depend upon a misregulation of the pathways which sustain neurodevelopmental control. In this context, this review article focuses on Friedreich ataxia (FA), a neurodegenerative disorder resulting from mutations within the gene encoding the Frataxin protein, which is involved in the control of mitochondrial function and oxidative metabolism. OBJECTIVE: The specific aim of the present study concerns the FA molecular and cellular substrates, for which available transgenic mice models are proposed, including mutants undergoing misexpression of adhesive/morphoregulatory proteins, in particular belonging to the Contactin subset of the immunoglobulin supergene family. METHODS: In both mutant and control mice, neurogenesis was explored by morphological/morphometric analysis through the expression of cell type-specific markers, including -tubulin, the Contactin-1 axonal adhesive glycoprotein, as well as the Glial Fibrillary Acidic Protein (GFAP). RESULTS: Specific consequences were found to arise from the chosen misexpression approach, consisting of a neuronal developmental delay associated with glial upregulation. Protective effects against the arising phenotype resulted from antioxidants (essentially epigallocatechin gallate (EGCG)) administration, which was demonstrated through the profiles of neuronal (-tubulin and Contactin 1) as well as glial (GFAP) markers, in turn indicating the concomitant activation of neurodegeneration and neuro repair processes. The latter also implied activation of the Notch-1 signaling. CONCLUSION: Overall, this study supports the significance of changes in morphoregulatory proteins expression in the FA pathogenesis and of antioxidant administration in counteracting it, which, in turn, allows to devise potential therapeutic approaches.

4.
Cells ; 11(10)2022 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-35626743

RESUMO

Successful neuroprotection is only possible with contemporary microvascular protection. The prevention of disease-induced vascular modifications that accelerate brain damage remains largely elusive. An improved understanding of pericyte (PC) signalling could provide important insight into the function of the neurovascular unit (NVU), and into the injury-provoked responses that modify cell-cell interactions and crosstalk. Due to sharing the same basement membrane with endothelial cells, PCs have a crucial role in the control of endothelial, astrocyte, and oligodendrocyte precursor functions and hence blood-brain barrier stability. Both cerebrovascular and neurodegenerative diseases impair oxygen delivery and functionally impair the NVU. In this review, the role of PCs in central nervous system health and disease is discussed, considering their origin, multipotency, functions and also dysfunction, focusing on new possible avenues to modulate neuroprotection. Dysfunctional PC signalling could also be considered as a potential biomarker of NVU pathology, allowing us to individualize therapeutic interventions, monitor responses, or predict outcomes.


Assuntos
Células Endoteliais , Pericitos , Astrócitos , Barreira Hematoencefálica/patologia , Comunicação Celular , Células Endoteliais/fisiologia , Pericitos/patologia
5.
Front Syst Neurosci ; 15: 650614, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34421548

RESUMO

In the central nervous system (CNS), dopamine (DA) is involved in motor and cognitive functions. Although the cerebellum is not been considered an elective dopaminergic region, studies attributed to it a critical role in dopamine deficit-related neurological and psychiatric disorders [e.g., Parkinson's disease (PD) and schizophrenia (SCZ)]. Data on the cerebellar dopaminergic neuronal system are still lacking. Nevertheless, biochemical studies detected in the mammalians cerebellum high dopamine levels, while chemical neuroanatomy studies revealed the presence of midbrain dopaminergic afferents to the cerebellum as well as wide distribution of the dopaminergic receptor subtypes (DRD1-DRD5). The present review summarizes the data on the cerebellar dopaminergic system including its involvement in associative and projective circuits. Furthermore, this study also briefly discusses the role of the cerebellar dopaminergic system in some neurologic and psychiatric disorders and suggests its potential involvement as a target in pharmacologic and non-pharmacologic treatments.

6.
Molecules ; 25(18)2020 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-32906751

RESUMO

In this study, the neural phenotype is explored in rodent models of the spinocerebellar disorder known as the Friedreich Ataxia (FA), which results from mutations within the gene encoding the Frataxin mitochondrial protein. For this, the M12 line, bearing a targeted mutation, which disrupts the Frataxin gene exon 4 was used, together with the M02 line, which, in addition, is hemizygous for the human Frataxin gene mutation (Pook transgene), implying the occurrence of 82-190 GAA repeats within its first intron. The mutant mice phenotype was compared to the one of wild type littermates in regions undergoing differential profiles of neurogenesis, including the cerebellar cortex and the spinal cord by using neuronal (ß-tubulin) and glial (Glial Fibrillary Acidic Protein) markers as well as the Contactin 1 axonal glycoprotein, involved in neurite growth control. Morphological/morphometric analyses revealed that while in Frataxin mutant mice the neuronal phenotype was significantly counteracted, a glial upregulation occurred at the same time. Furthermore, Contactin 1 downregulation suggested that changes in the underlying gene contributed to the disorder pathogenesis. Therefore, the FA phenotype implies an alteration of the developmental profile of neuronal and glial precursors. Finally, epigallocatechin gallate polyphenol administration counteracted the disorder, indicating protective effects of antioxidant administration.


Assuntos
Contactinas/genética , Suscetibilidade a Doenças , Ataxia de Friedreich/genética , Ataxia de Friedreich/metabolismo , Expressão Gênica , Animais , Antioxidantes/administração & dosagem , Comunicação Celular , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Contactinas/metabolismo , Modelos Animais de Doenças , Humanos , Imuno-Histoquímica , Camundongos , Mutação , Neuroglia/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fenótipo , Transdução de Sinais , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo
7.
Front Cell Dev Biol ; 7: 119, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31380366

RESUMO

In this study the mechanisms are explored, which modulate expression and function of cell surface adhesive glycoproteins of the Immunoglobulin Supergene Family (IgSF), and in particular of its Contactin subset, during neuronal precursor developmental events. In this context, a specific topic concerns the significance of the expression profile of such molecules and their ability to modulate signaling pathways activated through nutraceuticals, in particular polyphenols, administration. Both in vitro and in vivo approaches are chosen. As for the former, by using as a model the human SH-SY5Y neuroblastoma line, the effects of grape seed polyphenols are evaluated on proliferation and commitment/differentiation events along the neuronal lineage. In SH-SY5Y cell cultures, polyphenols were found to counteract precursor proliferation while promoting their differentiation, as deduced by studying their developmental parameters through the expression of cell cycle and neuronal commitment/differentiation markers as well as by measuring neurite growth. In such cultures, Cyclin E expression and BrdU incorporation were downregulated, indicating reduced precursor proliferation while increased neuronal differentiation was inferred from upregulation of cell cycle exit (p27-Kip) and neuronal commitment (NeuN) markers as well as by measuring neurite length through morphometric analysis. The polyphenol effects on developmental parameters were also explored in vivo, in cerebellar cortex, by using as a model the TAG/F3 transgenic line, which undergoes delayed neural development as a consequence of Contactin1 adhesive glycoprotein upregulation and premature expression under control of the Contactin2 gene (Cntn-2) promoter. In this transgenic line, a Notch pathway activation is known to occur and polyphenol treatment was found to counteract such an effect, demonstrated through downregulation of the Hes-1 transcription factor. Polyphenols also downregulated the expression of adhesive glycoproteins of the Contactin family themselves, demonstrated for both Contactin1 and Contactin2, indicating the involvement of changes in the expression of the underlying genes in the observed phenotype. These data support the hypothesis that the complex control exerted by polyphenols on neural development involves modulation of expression and function of the genes encoding cell adhesion molecules of the Contactin family and of the associated signaling pathways, indicating potential mechanisms whereby such compounds may control neurogenesis.

8.
Cerebellum ; 18(6): 999-1010, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31273610

RESUMO

The collier/Olf1/EBF family genes encode helix-loop-helix transcription factors (TFs) highly conserved in evolution, initially characterized for their roles in the immune system and in various aspects of neural development. The Early B cell Factor 2 (Ebf2) gene plays an important role in the establishment of cerebellar cortical topography and in Purkinje cell (PC) subtype specification. In the adult cerebellum, Ebf2 is expressed in zebrin II (ZII)-negative PCs, where it suppresses the ZII+ molecular phenotype. However, it is not clear whether Ebf2 is restricted to a PC subset from the onset of its expression or is initially distributed in all PCs and silenced only later in the prospective ZII+ subtype. Moreover, the dynamic distribution and role of Ebf2 in the differentiation of other cerebellar cells remain unclarified. In this paper, by genetic fate mapping, we determine that Ebf2 mRNA is initially found in all PC progenitors, suggesting that unidentified upstream factors silence its expression before completion of embryogenesis. Moreover we show Ebf2 activation in an early born subset of granule cell (GC) precursors homing in the anterior lobe. Conversely, Ebf2 transcription is repressed in other cerebellar cortex interneurons. Last, we show that, although Ebf2 only labels the medial cerebellar nuclei (CN) in the adult cerebellum, the gene is expressed prenatally in projection neurons of all CN. Importantly, in Ebf2 nulls, fastigial nuclei are severely hypocellular, mirroring the defective development of anterior lobe PCs. Our findings further clarify the roles of this terminal selector gene in cerebellar development.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/biossíntese , Cerebelo/embriologia , Cerebelo/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Sobrevivência Celular/fisiologia , Cerebelo/crescimento & desenvolvimento , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Células de Purkinje/metabolismo
9.
Molecules ; 24(12)2019 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-31212848

RESUMO

BACKGROUND: In mice, postnatal immune development has previously been investigated, and evidence of a delayed maturation of the adaptive immune response has been detected. METHODS: In this study, the effects of red grape polyphenol oral administration on the murine immune response were explored using pregnant mice (TAG/F3 transgenic and wild type (wt) mice) as the animal model. The study was performed during pregnancy as well as during lactation until postnatal day 8. Suckling pups from polyphenol-administered dams as well as day 30 post-weaning pups (dietary-administered with polyphenols) were used. Polyphenol effects were evaluated, measuring splenic cytokine secretion. RESULTS: Phorbol myristate acetate-activated splenocytes underwent the highest cytokine production at day 30 in both wt and TAG/F3 mice. In the latter, release of interferon (IFN)-γ and tumor necrosis factor (TNF)-α was found to be higher than in the wt counterpart. In this context, polyphenols exerted modulating activities on day 30 TAG/F3 mice, inducing release of interleukin (IL)-10 in hetero mice while abrogating release of IL-2, IFN-γ, TNF-α, IL-6, and IL-4 in homo and hetero mice. CONCLUSION: Polyphenols are able to prevent the development of an inflammatory/allergic profile in postnatal TAG/F3 mice.


Assuntos
Contactina 1/genética , Citocinas/metabolismo , Expressão Gênica , Polifenóis/farmacologia , Baço/efeitos dos fármacos , Baço/metabolismo , Desmame , Animais , Animais Recém-Nascidos , Camundongos , Camundongos Transgênicos , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
10.
Mol Cell Neurosci ; 81: 64-71, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28038945

RESUMO

Cell adhesion molecules (CAMs) have a pivotal role in building and maintaining synaptic structures during brain development participating in axonal elongation and pathfinding, glial guidance of neuronal migration, as well as myelination. CAMs expression persists in the adult brain particularly in structures undergoing postnatal neurogenesis and involved in synaptic plasticity and memory as the hippocampus. Among the neural CAMs, we have recently focused on F3/Contactin, a glycosylphosphatidyl inositol-anchored glycoprotein belonging to the immunoglobulin superfamily, involved in neuronal development, synaptic maintenance and organization of neuronal networks. Here, we discuss our recent data suggesting that F3/Contactin exerts a role in hippocampal synaptic plasticity and memory in adult and aged mice. In particular, we have studied long-term potentiation (LTP), spatial and object recognition memory, and phosphorylation of the transcription factor cAMP-Responsive-Element Binding protein (CREB) in a transgenic mouse model of F3/Contactin overexpression. We also investigated whether F3/Contactin might influence neuronal apoptosis and the production of amyloid-beta peptide (Aß), known to be one of the main pathogenetic hallmarks of Alzheimer's disease (AD). In conclusion, a further understanding of F3/Contactin role in synaptic plasticity and memory might have interesting clinical outcomes in cognitive disorders, such as aging and AD, offering innovative therapeutic opportunities.


Assuntos
Contactina 1/metabolismo , Memória , Plasticidade Neuronal , Animais , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Encéfalo/fisiologia , Disfunção Cognitiva/genética , Disfunção Cognitiva/metabolismo , Contactina 1/genética , Humanos
11.
Mol Cell Neurosci ; 81: 49-63, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-27871938

RESUMO

This review article focuses on the Contactin (CNTN) subset of the Immunoglobulin supergene family (IgC2/FNIII molecules), whose components share structural properties (the association of Immunoglobulin type C2 with Fibronectin type III domains), as well as a general role in cell contact formation and axonal growth control. IgC2/FNIII molecules include 6 highly related components (CNTN 1-6), associated with the cell membrane via a Glycosyl Phosphatidyl Inositol (GPI)-containing lipid tail. Contactin 1 and Contactin 2 share ~50 (49.38)% identity at the aminoacid level. They are components of the cell surface, from which they may be released in soluble forms. They bind heterophilically to multiple partners in cis and in trans, including members of the related L1CAM family and of the Neurexin family Contactin-associated proteins (CNTNAPs or Casprs). Such interactions are important for organising the neuronal membrane, as well as for modulating the growth and pathfinding of axon tracts. In addition, they also mediate the functional maturation of axons by promoting their interactions with myelinating cells at the nodal, paranodal and juxtaparanodal regions. Such interactions also mediate differential ionic channels (both Na+ and K+) distribution, which is of critical relevance in the generation of the peak-shaped action potential. Indeed, thanks to their interactions with Ankyrin G, Na+ channels map within the nodal regions, where they drive axonal depolarization. However, no ionic channels are found in the flanking Contactin1-containing paranodal regions, where CNTN1 interactions with Caspr1 and with the Ig superfamily component Neurofascin 155 in cis and in trans, respectively, build a molecular barrier between the node and the juxtaparanode. In this region K+ channels are clustered, depending upon molecular interactions with Contactin 2 and with Caspr2. In addition to these functions, the Contactins appear to have also a role in degenerative and inflammatory disorders: indeed Contactin 2 is involved in neurodegenerative disorders with a special reference to the Alzheimer disease, given its ability to work as a ligand of the Alzheimer Precursor Protein (APP), which results in increased Alzheimer Intracellular Domain (AICD) release in a γ-secretase-dependent manner. On the other hand Contactin 1 drives Notch signalling activation via the Hes pathway, which could be consistent with its ability to modulate neuroinflammation events, and with the possibility that Contactin 1-dependent interactions may participate to the pathogenesis of the Multiple Sclerosis and of other inflammatory disorders.


Assuntos
Axônios/metabolismo , Contactinas/metabolismo , Transtornos do Neurodesenvolvimento/metabolismo , Neurogênese , Animais , Contactinas/química , Contactinas/genética , Humanos , Transtornos do Neurodesenvolvimento/genética
12.
Dev Neurobiol ; 75(12): 1420-40, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25820347

RESUMO

The Contactin-1 axonal glycoprotein (formerly F3/Contactin) plays a relevant role in cerebellar ontogenesis, as shown in Contactin-1 KO-mice and in transgenic mice misexpressing the corresponding cDNA from a heterologous promoter. Likewise, null mutant mice for the Collier/Olf1/Early B-cell family transcription factor EBF2, in which Purkinje neuron development is primarily affected, exhibit abnormalities in cerebellar corticogenesis. Here, to evaluate the contribution to the Ebf2 null phenotype of changes in the profile of Contactin-1, we study its expression in Ebf2 null mice. In addition, we explore the activation profile of the Cntn1 gene promoter upon transferring the Ebf2 mutation to transgenic mice expressing an enhanced green fluorescent protein reporter under control of Cntn1 gene regulatory sequences. In Ebf2 null mice, Contactin-1 protein expression and Cntn1 gene promoter activity are both downregulated during embryonic and early postnatal cerebellar development, both in the rostral and caudal folia, while in the latter an upregulation is observed at postnatal day 8. In vitro, vectors driving EBF1,2,3 transcription factors from a cytomegalovirus (CMV) promoter transactivate a Cntn1-Choline acetyltransferse (CAT) promoter-reporter construct in cotransfection assays and, accordingly, by chromatin immunoprecipitation, we show that the Cntn1 gene 5' flanking region is bound by the EBF2 transcription factor, consistent with the evidence that this region bears the cognate deoxyribonucleic acid (DNA) consensus sequences. These data indicate that Contactin-1 expression is dependent upon EBF factors, suggesting that the Cntn1 gene belongs to the expanding regulatory cascade driven by these transcriptional regulators so that changes in its activation may contribute to the phenotype of Ebf2 null mutant mice.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Cerebelo/crescimento & desenvolvimento , Cerebelo/metabolismo , Contactina 1/metabolismo , Transativadores/metabolismo , Animais , Sequência de Bases , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Western Blotting , Proliferação de Células/fisiologia , Cerebelo/citologia , Colina O-Acetiltransferase/genética , Colina O-Acetiltransferase/metabolismo , Contactina 1/genética , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Imuno-Histoquímica , Imunoprecipitação , Camundongos Transgênicos , Dados de Sequência Molecular , Regiões Promotoras Genéticas , Alinhamento de Sequência , Transfecção
13.
Neurobiol Aging ; 36(4): 1702-1715, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25659859

RESUMO

We have recently shown that overexpression of the F3/contactin adhesive glycoprotein (also known as Contactin-1) promotes neurogenesis in adult hippocampus, which correlates with improved synaptic plasticity and memory. Because F3/contactin levels physiologically decrease with age, here, we aim at investigating whether its overexpression might counteract the cognitive decline in aged animals. For this we use 20- to 24-month-old TAG/F3 transgenic mice in which F3/contactin overexpression is driven by regulatory sequences from the gene encoding the transient axonal glycoprotein TAG-1 throughout development. We show that aged TAG/F3 mice display improved hippocampal long-term potentiation and memory compared with wild-type littermates. The same mice undergo a decrease of neuronal apoptosis at the hippocampal level, which correlated to a decrease of active caspase-3; by contrast, procaspase-3 and Bax as well as the anti-apoptotic and plasticity-related pathway BDNF/CREB/Bcl-2 were rather increased. Interestingly, amyloid-precursor protein processing was shifted toward sAPPα generation, with a decrease of sAPPß and amyloid-beta levels. Our data confirm that F3/contactin plays a role in hippocampal synaptic plasticity and memory also in aged mice, suggesting that it acts on molecular pathways related to apoptosis and amyloid-beta production.


Assuntos
Envelhecimento/genética , Contactina 1/genética , Contactina 1/fisiologia , Hipocampo/fisiologia , Memória/fisiologia , Plasticidade Neuronal/genética , Plasticidade Neuronal/fisiologia , Envelhecimento/fisiologia , Envelhecimento/psicologia , Peptídeos beta-Amiloides/metabolismo , Animais , Apoptose/genética , Fator Neurotrófico Derivado do Encéfalo/fisiologia , Caspase 3/metabolismo , Transtornos Cognitivos/genética , Expressão Gênica , Hipocampo/patologia , Potenciação de Longa Duração/genética , Camundongos Transgênicos
14.
Hippocampus ; 23(12): 1367-82, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23939883

RESUMO

F3/contactin, a cell-adhesion molecule belonging to the immunoglobulin supergene family, is involved in several aspects of neural development including synapse building, maintenance and functioning. Here, we examine F3/contactin function in adult hippocampal neurogenesis, synaptic plasticity, and memory, using as a model TAG/F3 transgenic mice, where F3/contactin overexpression was induced under control of regulatory sequences from the human TAG-1 (TAX-1) gene. Transgenic mice aged 5 (M5) and 12 (M12) months exhibited an increase in hippocampal size, which correlated with positive effects on precursor proliferation and NeuN expression, these data suggesting a possible role for F3/contactin in promoting adult hippocampal neurogenesis. On the functional level, TAG/F3 mice exhibited increased CA1 long-term potentiation and improved spatial and object recognition memory, notably at 12 months of age. Interestingly, these mice showed an increased expression of the phosphorylated transcription factor CREB, which may represent the main molecular correlate of the observed morphological and functional effects. Altogether, these findings indicate for the first time that F3/contactin plays a role in promoting adult hippocampal neurogenesis and that this effect correlates with improved synaptic function and memory.


Assuntos
Contactina 1/metabolismo , Hipocampo/citologia , Potenciação de Longa Duração/genética , Memória/fisiologia , Neurogênese/genética , Fatores Etários , Animais , Bromodesoxiuridina/metabolismo , Proteína de Ligação a CREB/genética , Proteína de Ligação a CREB/metabolismo , Proliferação de Células , Contactina 1/genética , Estimulação Elétrica , Proteína Glial Fibrilar Ácida/metabolismo , Hipocampo/fisiologia , Técnicas In Vitro , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Técnicas de Patch-Clamp , Reconhecimento Psicológico/fisiologia
15.
Mol Cell Neurosci ; 50(3-4): 221-37, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22579730

RESUMO

F3/Contactin is a neuronal surface glycoprotein, which plays a general role in neural development and, in particular, in neuronal and oligodendrocyte differentiation. In a previous study using the F3/EGFP transgenic mice, which express an EGFP reporter under control of the regulatory region from the mouse F3/Contactin gene, the activation of the F3/Contactin promoter was found to correlate with granule and Purkinje neuron differentiation in developing cerebellar cortex. Here we report that in developing cerebral cortex and basal ganglia the F3/Contactin gene is mostly activated during early commitment of neuronal precursors, thus indicating a region-specific profile of its developmental activation. We also report that, in the same structures of F3/EGFP mice, a downregulation of the endogenous F3/Contactin gene occurs, which correlates with upregulation of the dopaminergic phenotype and with locomotor pattern abnormalities. Therefore, F3/EGFP transgenic mice exhibit morphological and functional phenotypes recapitulating those arising from imbalance of the striatal dopaminergic pathway. As for the underlying mechanisms, we postulate that in F3/EGFP mice F3/Contactin downregulation results from the ability of transgene promoter sequences to interfere with the activation of the endogenous gene, thus realizing an F3/Contactin knockdown model, while dopaminergic upregulation is consistent with a general F3/Contactin inhibitory effect on the neuronal phenotype.


Assuntos
Córtex Cerebral/metabolismo , Contactina 1/genética , Neurônios Dopaminérgicos/metabolismo , Regiões Promotoras Genéticas , Substância Negra/metabolismo , Animais , Córtex Cerebral/crescimento & desenvolvimento , Contactina 1/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Fluorescência Verde/genética , Camundongos , Camundongos Transgênicos , Proteínas Recombinantes de Fusão , Substância Negra/crescimento & desenvolvimento , Transcrição Gênica
16.
Dev Biol ; 365(1): 133-51, 2012 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-22360968

RESUMO

The expression of the cell recognition molecule F3/Contactin (CNTN1) is generally associated with the functions of post-mitotic neurons. In the embryonic cortex, however, we find it expressed by proliferating ventricular zone (VZ) precursors. In contrast to previous findings in the developing cerebellum, F3/Contactin transgenic overexpression in the early cortical VZ promotes proliferation and expands the precursor pool at the expense of neurogenesis. At later stages, when F3/Contactin levels subside, however, neurogenesis resumes, suggesting that F3/Contactin expression in the VZ is inversely related to neurogenesis and plays a role in a feedback control mechanism, regulating the orderly progression of cortical development. The modified F3/Contactin profile therefore results in delayed corticogenesis, as judged by downregulation in upper and lower layer marker expression and by BrdU birth dating, indicating that, in this transgenic model, increased F3/Contactin levels counteract neuronal precursor commitment. These effects also occur in primary cultures and are reproduced by addition of an F3/Fc fusion protein to wild type cultures. Together, these data indicate a completely novel function for F3/Contactin. Parallel changes in the generation of the Notch Intracellular Domain and in the expression of the Hes-1 transcription factor indicate that activation of the Notch pathway plays a role in this phenotype, consistent with previous in vitro reports that F3/Contactin is a Notch1 ligand.


Assuntos
Córtex Cerebral/embriologia , Contactina 1/fisiologia , Neurogênese , Animais , Animais Geneticamente Modificados , Diferenciação Celular , Córtex Cerebral/citologia , Córtex Cerebral/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Camundongos , Neurogênese/genética , Neurônios/citologia , Neurônios/fisiologia , Receptores Notch/fisiologia , Transdução de Sinais
17.
Immunopharmacol Immunotoxicol ; 33(1): 227-31, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20507213

RESUMO

Biological drugs targeting tumor necrosis factor-α, such as infliximab, are highly effective in psoriasis. The interference with keratinocyte apoptosis has been included among the possible effects of infliximab in psoriasis, although the available data are still controversial. The purpose of our study was to verify the action of infliximab on psoriatic keratinocytes. Keratinocyte apoptosis was evaluated in the lesional psoriatic skin of 11 patients at baseline and a different time point during treatment with infliximab. Infliximab (5 mg/kg) was given intravenously at weeks 0, 2, and 6, followed by maintenance infusions every 8 weeks. Pretreatment with intravenous hydrocortisone was performed prior to each infusion. Keratinocytes with apoptotic features were histologically identified according to the following changes: chromatin condensation at the periphery of the nucleus, cytoplasmic vesiculation, nuclear fragmentation, nuclear pyknosis. Immunohistochemical assessment of p53 and caspase-3 expression was also performed. At baseline, prior to treatment with infliximab, lesional epidermis showed 1.2-3.2% p53-positive apoptotic keratinocytes in the basal zone. The number of p53-positive apoptotic keratinocytes increased after treatment with infliximab, already at day 1-2 after the first infusion, and such cells were localized at basal and suprabasal layers or were through all layers. There was no immunoreactivity for caspase-3 at any time point examined. Our results suggest that induction of p53-related keratinocyte apoptosis might be one of the mechanisms of infliximab action in psoriasis.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Apoptose/efeitos dos fármacos , Queratinócitos/efeitos dos fármacos , Psoríase/tratamento farmacológico , Pele/efeitos dos fármacos , Adulto , Anticorpos Monoclonais/administração & dosagem , Caspase 3/biossíntese , Esquema de Medicação , Feminino , Humanos , Imuno-Histoquímica , Infliximab , Injeções Intravenosas , Queratinócitos/imunologia , Queratinócitos/patologia , Masculino , Pessoa de Meia-Idade , Psoríase/imunologia , Psoríase/patologia , Pele/imunologia , Pele/patologia , Fator de Necrose Tumoral alfa/imunologia , Proteína Supressora de Tumor p53/biossíntese , Adulto Jovem
18.
Cell Adh Migr ; 3(1): 53-63, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19372728

RESUMO

F3/Contactin is an immunoglobulin superfamily component expressed in the nervous tissue of several species. Here we focus on the structural and functional properties of its mouse relative, on the mechanisms driving its regulated expression and on its developmental role. F3/Contactin is differentially expressed in distinct populations of central and peripheral neurons and in some non-neuronal cells. Accordingly, the regulatory region of the underlying gene includes promoter elements undergoing differential activation, associated with an intricate splicing profile, indicating that transcriptional and posttranscriptional mechanisms contribute to its expression. Transgenic models allowed to follow F3/Contactin promoter activation in vivo and to modify F3/Contactin gene expression under a heterologous promoter, which resulted in morphological and functional phenotypes. Besides axonal growth and pathfinding, these concerned earlier events, including precursor proliferation and commitment. This wide role in neural ontogenesis is consistent with the recognized interaction of F3/Contactin with developmental control genes belonging to the Notch pathway.


Assuntos
Moléculas de Adesão Celular Neuronais/química , Moléculas de Adesão Celular Neuronais/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Glicoproteínas/química , Glicoproteínas/metabolismo , Animais , Moléculas de Adesão Celular Neuronais/genética , Contactinas , Glicoproteínas/genética , Camundongos
19.
Neurotoxicol Teratol ; 30(5): 395-403, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18495421

RESUMO

Neurofunctional effects produced by gestational all-trans retinoic acid (all-trans RA) treatment were investigated in the offspring of Sprague-Dawley rats. Reproduction data, onset of reflexive behavior, locomotor activity, motor coordination and motor learning were examined. Moreover, possible changes in size and morphology of the cerebellum were evaluated. The results show that all-trans RA treatment (2.5 mg/kg, by gavage) on gestational days (GD) 11-13 significantly increased postnatal mortality and decreased pup weight gain. Moreover, all-trans RA-treated rats showed a significant delay in eyes opening, hair growth as well as in the maturation of righting reflex, cliff aversion and pole grasping. All-trans RA treatment significantly impaired the ambulatory activity in adult rats without altering the number of rearings. All-trans RA-treated rats subjected to the rotarod/accelerod task showed significant impairment in both motor coordination and motor learning ability. The morphological analysis revealed a significant reduction in the cerebellar size and impairment in foliation profile, at PND 3 with subsequent recovery at PNDs 8 and 40. The evidence that functional alterations increase with age and persist in adulthood whereas the morphological changes decline with age, strongly supports the view that, besides the cerebellum morphology, the organization of the cerebellar circuitry, and in particular of cortico-cerebellar connections, are also affected by all-trans RA treatment.


Assuntos
Cerebelo/anormalidades , Cerebelo/efeitos dos fármacos , Malformações do Sistema Nervoso/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Teratogênicos/toxicidade , Tretinoína/toxicidade , Administração Oral , Animais , Antineoplásicos/toxicidade , Peso Corporal/efeitos dos fármacos , Cerebelo/patologia , Discinesia Induzida por Medicamentos/fisiopatologia , Feminino , Deficiências da Aprendizagem/induzido quimicamente , Deficiências da Aprendizagem/fisiopatologia , Masculino , Atividade Motora/efeitos dos fármacos , Transtornos das Habilidades Motoras/induzido quimicamente , Transtornos das Habilidades Motoras/fisiopatologia , Malformações do Sistema Nervoso/patologia , Malformações do Sistema Nervoso/fisiopatologia , Vias Neurais/anormalidades , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiopatologia , Fenótipo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/patologia , Ratos , Ratos Sprague-Dawley , Reprodução/efeitos dos fármacos , Caracteres Sexuais , Estereoisomerismo , Tempo
20.
J Neurosci Res ; 86(4): 821-31, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17941055

RESUMO

By using antibodies against mouse F3/contactin, we found immunologically related glycoproteins expressed in the nervous tissue of the snail Helix pomatia. Helix contactin-related proteins (HCRPs) include different molecules ranging in size from 90 to 240 kD. Clones isolated from a cDNA expression library allowed us to demonstrate that these proteins are translated from a unique 6.3-kb mRNA, suggesting that their heterogeneity depends on posttranslational processing. This is supported by the results of endoglycosidase F treatment, which indicate that the high-molecular-weight components are glycosylation variants of the 90-kD chain. In vivo and in cultures, HCRPs antibodies label neuronal soma and neurite extensions, giving the appearance of both cytoplasmic and cell surface immunostaining. On the other hand, no expression is found on nonneural tissues. Functionally, HCRPs are involved in neurite growth control and appear to modulate neurotransmitter release, as indicated by the inhibiting effects of specific antibodies on both functions. These data allow the definition of HCRPs glycoproteins as growth-promoting molecules, suggesting that they play a role in neurite development and presynaptic terminal maturation in the invertebrate nervous system.


Assuntos
Moléculas de Adesão Celular Neuronais/metabolismo , Gânglios dos Invertebrados/metabolismo , Caracois Helix/fisiologia , Neuritos/metabolismo , Neurotransmissores/metabolismo , Animais , Northern Blotting , Western Blotting , Clonagem Molecular , Contactinas , Biblioteca Gênica , Imuno-Histoquímica , Camundongos , RNA Mensageiro
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