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1.
Glycoconj J ; 37(6): 681-690, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33108606

RESUMO

In this study, we found that gene expression of the human ß-galactoside α2,6-sialyltransferase (hST6Gal I) was specifically increased during differentiation of human MG-63 osteoblastic cells by serum starvation (SS). In parallel, a distinct increase in binding to SNA, the α2,6-sialyl-specific lectin, was observed in serum-starved cells, as demonstrated by FACS analysis. 5'-Rapid amplification of cDNA ends analysis demonstrated that the increase of hST6Gal I transcript by SS is mediated by P1 promoter. To elucidate transcriptional regulation of hST6Gal I in SS-induced MG-63 cells, we functionally characterized the P1 promoter region of the hST6Gal I gene. The 5'-deletion analysis of P1 promoter region revealed that the 189 bp upstream region of transcription start site is critical for transcriptional activity of hST6Gal I gene in SS-induced MG-63 cells. This region contains the predicted binding sites for several transcription factors, including AREB6, FOXP1, SIX3, HNF1, YY2, and MOK2. The mutagenesis analysis for these sites and chromatin immunoprecipitation assay demonstrated that the YY2 binding site at -98 to -77 was essential for the SS-induced hST6Gal I gene expression during differentiation of MG-63 cells.


Assuntos
Antígenos CD/genética , Diferenciação Celular/genética , Osteoblastos/citologia , Sialiltransferases/genética , Transcrição Gênica , Proteínas de Ligação a DNA/genética , Proteínas do Olho/genética , Fatores de Transcrição Forkhead/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Regulação Enzimológica da Expressão Gênica/genética , Proteínas de Homeodomínio/genética , Humanos , Proteínas do Tecido Nervoso/genética , Osteoblastos/metabolismo , Regiões Promotoras Genéticas/genética , Proteínas Repressoras/genética , Fatores de Transcrição/genética , Sítio de Iniciação de Transcrição , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Proteína Homeobox SIX3
2.
Proc Natl Acad Sci U S A ; 116(47): 23636-23642, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31685615

RESUMO

Sonic hedgehog (SHH) signaling plays a pivotal role in 2 different phases during brain development. Early SHH signaling derived from the prechordal plate (PrCP) triggers secondary Shh induction in the forebrain, which overlies the PrCP, and the induced SHH signaling, in turn, directs late neuronal differentiation of the forebrain. Consequently, Shh regulation in the PrCP is crucial for initiation of forebrain development. However, no enhancer that regulates prechordal Shh expression has yet been found. Here, we identified a prechordal enhancer, named SBE7, in the vicinity of a cluster of known forebrain enhancers for Shh This enhancer also directs Shh expression in the ventral midline of the forebrain, which receives the prechordal SHH signal. Thus, the identified enhancer acts not only for the initiation of Shh regulation in the PrCP but also for subsequent Shh induction in the forebrain. Indeed, removal of the enhancer from the mouse genome markedly down-regulated the expression of Shh in the rostral domains of the axial mesoderm and in the ventral midline of the forebrain and hypothalamus in the mouse embryo, and caused a craniofacial abnormality similar to human holoprosencephaly (HPE). These findings demonstrate that SHH signaling mediated by the newly identified enhancer is essential for development and growth of the ventral midline of the forebrain and hypothalamus. Understanding of the Shh regulation governed by this prechordal and brain enhancer provides an insight into the mechanism underlying craniofacial morphogenesis and the etiology of HPE.


Assuntos
Elementos Facilitadores Genéticos , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Hedgehog/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Prosencéfalo/embriologia , Animais , Sistemas CRISPR-Cas , Proteínas do Olho/fisiologia , Técnicas de Inativação de Genes , Genes Reporter , Proteínas Hedgehog/biossíntese , Proteínas Hedgehog/genética , Holoprosencefalia/genética , Proteínas de Homeodomínio/fisiologia , Hipotálamo/anormalidades , Hipotálamo/embriologia , Hipotálamo/metabolismo , Óperon Lac , Mesencéfalo/embriologia , Mesencéfalo/metabolismo , Mesoderma/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Prosencéfalo/anormalidades , Prosencéfalo/metabolismo , Transdução de Sinais , Transgenes , Proteína Homeobox SIX3
3.
Dev Biol ; 439(2): 102-111, 2018 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-29679559

RESUMO

Although the hypothalamus functions as a master homeostat for many behaviors, little is known about the transcriptional networks that control its development. To investigate this question, we analyzed mice deficient for the Forkhead domain transcription factor Foxd1. Foxd1 is selectively expressed in neuroepithelial cells of the prethalamus and hypothalamus prior to the onset of neurogenesis, and is later restricted to neural progenitors of the prethalamus and anterior hypothalamus. During early stages of neurogenesis, we observed that Foxd1-deficient mice showed reduced expression of Six3 and Vax1 in anterior hypothalamus, but overall patterning of the prethalamus and hypothalamus is unaffected. After neurogenesis is complete, however, a progressive reduction and eventual loss of expression of molecular markers of the suprachiasmatic, paraventricular and periventricular hypothalamic is observed. These findings demonstrate that Foxd1 acts in hypothalamic progenitors to allow sustained expression of a subset of genes selectively expressed in mature neurons of the anterior hypothalamus.


Assuntos
Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Animais , Núcleo Hipotalâmico Anterior/metabolismo , Núcleo Hipotalâmico Anterior/fisiologia , Padronização Corporal/genética , Diferenciação Celular/genética , Proteínas do Olho/genética , Proteínas do Olho/metabolismo , Fatores de Transcrição Forkhead/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/genética , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Hipotálamo/metabolismo , Camundongos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurogênese/fisiologia , Neurônios/metabolismo , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Células-Tronco/metabolismo , Células-Tronco/fisiologia , Fatores de Transcrição/metabolismo , Proteína Homeobox SIX3
4.
Dev Biol ; 396(1): 136-49, 2014 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-25263198

RESUMO

The apical plate of primary marine larvae is characterized by a common set of transcription factors comprising six3, rx, hbn, nk2.1 and FoxQ2. It harbours the apical organ, a neural and ciliary structure with neurosecretory properties. Recent studies in lophotrochozoans have found that apical organ cells form the anterior tip of the developing central nervous system. We identify an anterior medial tissue in the embryonic centipede head that shares the transcriptional profile of the apical plate of marine larvae, including nested domains of FoxQ2 and six3 expression. This domain gives rise to an anterior medial population of neural precursors distinct from those arising within the segmental neuroectoderm. These medial cells do not express achaete scute homologue in proneural clusters, but express collier, a marker for post mitotic cells committed to a neural fate, while they are still situated in the surface ectodermal layer. They then sink under the surface to form a compact cell cluster. Once internalized these cells extend axons that pioneer the primary axonal scaffold of the central nervous system. The same cells express phc2, a neural specific prohormone convertase, which suggests that they form an early active neurosecretory centre. Some also express markers of hypothalamic neurons, including otp, vtn and vax1. These medial neurosecretory cells of the centipede are distinct from those of the pars intercerebralis, the anterior neurosecretory part of the insect brain. The pars intercerebralis derives from vsx positive placodal-like invagination sites. In the centipede, vsx expressing invaginating ectoderm is situated bilaterally adjacent to the medial pioneer cell population. Hence the pars intercerebralis is present in both insect and centipede brains, whereas no prominent anterior medial cluster of pioneer neurons is present in insects. These observations suggest that the arthropod brain retained ancestrally an anterior medial population of neurosecretory cells homologous to those of the apical plate in other invertebrate phyla, but that this cell population has been lost or greatly reduced in insects.


Assuntos
Artrópodes/embriologia , Sistema Nervoso Central/embriologia , Regulação da Expressão Gênica no Desenvolvimento , Animais , Axônios/fisiologia , Blastoderma/fisiologia , Encéfalo/embriologia , Diferenciação Celular , Linhagem da Célula , Proteínas do Olho/fisiologia , Proteínas de Homeodomínio/fisiologia , Hipotálamo/embriologia , Larva/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Neurônios/citologia , Neurônios/fisiologia , Fatores de Tempo , Transcrição Gênica , Proteína Homeobox SIX3
5.
Neural Dev ; 4: 19, 2009 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-19500363

RESUMO

BACKGROUND: In addition to its well-known expression in dorsal telencephalic progenitor cells, where it regulates cell proliferation and identity, the transcription factor Pax6 is expressed in some ventral telencephalic cells, including many postmitotic neurons. Its functions in these cells are unknown. RESULTS: We generated a new floxed allele of Pax6 and tested the consequences of a highly specific ventral telencephalic depletion of Pax6. We used the Six3A1A2-Cre allele that drives production of Cre recombinase in a specific region of Pax6-expression close to the internal capsule, through which thalamic axons navigate to cerebral cortex. Depletion in this region caused many thalamic axons to take aberrant routes, either failing to turn normally into ventral telencephalon to form the internal capsule or exiting the developing internal capsule ventrally. We tested whether these defects might have resulted from abnormalities of two structural features proposed to guide thalamic axons into and through the developing internal capsule. First, we looked for the early pioneer axons that project from the region of the future internal capsule to the thalamus and are thought to guide thalamocortical axons to the internal capsule: we found that they are present in conditional mutants. Second, we examined the development of the corridor of Islet1-expressing cells that guides thalamic axons through ventral telencephalon and found that it was broader and less dense than normal in conditional mutants. We also examined corticofugal axons that are thought to interact with ascending thalamocortical axons, resulting in each set providing guidance to the other, and found that some are misrouted to lateral telencephalon. CONCLUSION: These findings indicate that ventral telencephalic Pax6 is important for formation of the Islet1-expressing corridor and the thalamic and cortical axons that grow through it. We suggest that Pax6 might affect thalamic axonal growth indirectly via its effect on the corridor.


Assuntos
Axônios/fisiologia , Córtex Cerebral/embriologia , Proteínas do Olho/metabolismo , Proteínas de Homeodomínio/metabolismo , Neurônios/citologia , Fatores de Transcrição Box Pareados/metabolismo , Proteínas Repressoras/metabolismo , Telencéfalo , Tálamo/embriologia , Fatores Etários , Fosfatase Alcalina/genética , Fosfatase Alcalina/metabolismo , Animais , Córtex Cerebral/citologia , Proteínas do Ovo/genética , Embrião de Mamíferos , Proteínas do Olho/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Proteínas de Homeodomínio/genética , Humanos , Íntrons/genética , Glicoproteínas de Membrana/deficiência , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos ICR , Camundongos Knockout , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Vias Neurais/embriologia , Fator de Transcrição PAX6 , Fatores de Transcrição Box Pareados/deficiência , Receptores de Superfície Celular/deficiência , Receptores de Superfície Celular/genética , Telencéfalo/citologia , Telencéfalo/embriologia , Telencéfalo/metabolismo , Tálamo/citologia , Glicoproteínas da Zona Pelúcida , Proteína Homeobox SIX3
6.
Nat Genet ; 40(11): 1348-53, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18836447

RESUMO

In humans, SHH haploinsufficiency results in holoprosencephaly (HPE), a defect in anterior midline formation. Despite the importance of maintaining SHH transcript levels above a critical threshold, we know little about the upstream regulators of SHH expression in the forebrain. Here we describe a rare nucleotide variant located 460 kb upstream of SHH in an individual with HPE that resulted in the loss of Shh brain enhancer-2 (SBE2) activity in the hypothalamus of transgenic mouse embryos. Using a DNA affinity-capture assay, we screened the SBE2 sequence for DNA-binding proteins and identified members of the Six3 and Six6 homeodomain family as candidate regulators of Shh transcription. Six3 showed reduced binding affinity for the mutant compared to the wild-type SBE2 sequence. Moreover, Six3 with HPE-causing alterations failed to bind and activate SBE2. These data suggest a direct link between Six3 and Shh regulation during normal forebrain development and in the pathogenesis of HPE.


Assuntos
Proteínas do Olho/metabolismo , Proteínas Hedgehog/metabolismo , Proteínas de Homeodomínio/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Animais , Sequência de Bases , Células COS , Chlorocebus aethiops , Proteínas Hedgehog/genética , Holoprosencefalia/genética , Holoprosencefalia/patologia , Humanos , Hipotálamo/metabolismo , Camundongos , Dados de Sequência Molecular , Mutação/genética , Ligação Proteica , Transativadores , Proteína Homeobox SIX3
7.
Development ; 135(3): 441-50, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18094027

RESUMO

The homeobox gene Six3 represses Wnt1 transcription. It is also required in the anterior neural plate for the development of the mammalian rostral forebrain. We have now determined that at the 15- to 17-somite stage, the prospective diencephalon is the most-anterior structure in the Six3-null brain, and Wnt1 expression is anteriorly expanded. Consequently, the brain caudalizes, and at the 22- to 24-somite stage, the prospective thalamic territory is the most-anterior structure. At around E11.0, the pretectum replaces this structure. Analysis of Six3;Wnt1 double-null mice revealed that Six3-mediated repression of Wnt1 is necessary for the formation of the rostral diencephalon and that Six3 activity is required for the formation of the telencephalon. These results provide insight into the mechanisms that establish anteroposterior identity in the developing mammalian brain.


Assuntos
Padronização Corporal , Diencéfalo/embriologia , Proteínas do Tecido Nervoso/deficiência , Animais , Diencéfalo/metabolismo , Embrião de Mamíferos/embriologia , Embrião de Mamíferos/metabolismo , Proteínas do Olho/genética , Proteínas do Olho/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Camundongos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Repressoras/metabolismo , Somitos/embriologia , Somitos/metabolismo , Telencéfalo/embriologia , Telencéfalo/metabolismo , Tálamo/embriologia , Tálamo/metabolismo , Proteínas Wnt/metabolismo , Proteína Homeobox SIX3
8.
Genomics ; 61(1): 82-91, 1999 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-10512683

RESUMO

The Drosophila gene sine oculis (so), a nuclear homeoprotein that is required for eye development, has several homologues in vertebrates (the SIX gene family). Among them, SIX3 is considered to be the functional orthologue of so because it is strongly expressed in the developing eye. However, embryonic SIX3 expression is not limited to the eye field, and SIX3 has been found to be mutated in some patients with holoprosencephaly type 2 (HPE2), suggesting that SIX3 has wide implications in head development. We report here the cloning and characterization of SIX6, a novel human SIX gene that is the homologue of the chick Six6(Optx2) gene. SIX6 is closely related to SIX3 and is expressed in the developing and adult human retina. Data from chick and mouse suggest that the human SIX6 gene is also expressed in the hypothalamic and the pituitary regions. SIX6 spans 2567 bp of genomic DNA and is split in two exons that are transcribed into a 1393-nucleotide-long mRNA. Chromosomal mapping of SIX6 revealed that it is closely linked to SIX1 and SIX4 in human chromosome 14q22.3-q23, which provides clues about the origin and evolution of the vertebrate SIX family. Recently three independent reports have associated interstitial deletions at 14q22.3-q23 with bilateral anophthalmia and pituitary anomalies. Genomic analyses of one of these cases demonstrated SIX6 hemizygosity, strongly suggesting that SIX6 haploinsufficiency is responsible for these developmental disorders.


Assuntos
Anoftalmia/genética , Cromossomos Humanos Par 14 , Genes Homeobox , Proteínas de Homeodomínio/genética , Família Multigênica , Proteínas do Tecido Nervoso/genética , Hipófise/anormalidades , Sequência de Aminoácidos , Animais , Anoftalmia/embriologia , Embrião de Galinha , Criança , Clonagem Molecular , Evolução Molecular , Proteínas do Olho , Feminino , Feto/anormalidades , Humanos , Hipotálamo/metabolismo , Masculino , Dados de Sequência Molecular , Hipófise/metabolismo , Retina/metabolismo , Proteína Homeobox SIX3
9.
Mech Dev ; 84(1-2): 31-40, 1999 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-10473118

RESUMO

We report on the isolation of a murine homeobox-containing gene, Six6 (Optx2), that shows extended identity in its coding region with Six3, the only member of the mammalian Six gene family known to be expressed in the optic primordium. Phylogenetic analysis demonstrates that Six6 and Six3 belong to a separate group of homeobox-genes that are closely related to the recently identified Drosophila optix. Earliest Six6 expression was detected in the floor of the diencephalic portion of the primitive forebrain, a region predicted to give rise to the neurohypophysis and to the hypothalamus. Later on, Six6 mRNA was found in the primordial tissues giving rise to the mature pituitary: the Rathke's pouch and the infundibular recess. In the optic primordium, Six6 demarcates the presumptive ventral optic stalk and the ventral portion of the future neural retina. In the developing eye. Six6 expression was detected in the neural retina, the optic chiasma and optic stalk, but not in the lens. When compared to Six6, Six3 expression pattern was highly similar, but with a generally broader transcripts distribution in the brain and in the visual system. We finally show that Six6 does not require Pax6 for its expression in the optic primordium, suggesting that Six6 acts on a parallel and/or independent pathway with Pax6 in the genetic cascade governing early development of the eye.


Assuntos
Proteínas de Homeodomínio/genética , Hipotálamo/embriologia , Quiasma Óptico/embriologia , Hipófise/embriologia , Transativadores/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Clonagem Molecular , Proteínas de Ligação a DNA/genética , Proteínas do Olho/genética , Proteínas do Olho/metabolismo , Proteínas de Homeodomínio/metabolismo , Hipotálamo/metabolismo , Camundongos , Camundongos Mutantes , Dados de Sequência Molecular , Mutação , Proteínas do Tecido Nervoso/genética , Quiasma Óptico/metabolismo , Fator de Transcrição PAX6 , Fatores de Transcrição Box Pareados , Filogenia , Hipófise/metabolismo , Proteínas Repressoras , Retina/embriologia , Retina/metabolismo , Homologia de Sequência de Aminoácidos , Transativadores/metabolismo , Córtex Visual/embriologia , Córtex Visual/metabolismo , Proteína Homeobox SIX3
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