RESUMO
The earliest known determinants of retinal nasotemporal identity are the transcriptional regulators Foxg1, which is expressed in the prospective nasal optic vesicle, and Foxd1, which is expressed in the prospective temporal optic vesicle. Previous work has shown that, in zebrafish, Fgf signals from the dorsal forebrain and olfactory primordia are required to specify nasal identity in the dorsal, prospective nasal, optic vesicle. Here, we show that Hh signalling from the ventral forebrain is required for specification of temporal identity in the ventral optic vesicle and is sufficient to induce temporal character when activated in the prospective nasal retina. Consequently, the evaginating optic vesicles become partitioned into prospective nasal and temporal domains by the opposing actions of Fgfs and Shh emanating from dorsal and ventral domains of the forebrain primordium. In absence of Fgf activity, foxd1 expression is established irrespective of levels of Hh signalling, indicating that the role of Shh in promoting foxd1 expression is only required in the presence of Fgf activity. Once the spatially complementary expression of foxd1 and foxg1 is established, the boundary between expression domains is maintained by mutual repression between Foxd1 and Foxg1.
Assuntos
Padronização Corporal/fisiologia , Fatores de Crescimento de Fibroblastos/metabolismo , Proteínas Hedgehog/metabolismo , Retina/embriologia , Transdução de Sinais/fisiologia , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/embriologia , Animais , Carbocianinas , Fatores de Transcrição Forkhead , Processamento de Imagem Assistida por Computador , Microscopia Confocal , Prosencéfalo/metabolismoRESUMO
Retina ganglion cell (RGC) axons grow along a stereotyped pathway undergoing coordinated rounds of fasciculation and defasciculation, which are critical to establishing proper eye-brain connections. How this coordination is achieved is poorly understood, but shedding of guidance cues by metalloproteinases is emerging as a relevant mechanism. Secreted Frizzled Related Proteins (Sfrps) are multifunctional proteins, which, among others, reorient RGC growth cones by regulating intracellular second messengers, and interact with Tolloid and ADAM metalloproteinases, thereby repressing their activity. Here, we show that the combination of these two functions well explain the axon guidance phenotype observed in Sfrp1 and Sfrp2 single and compound mouse mutant embryos, in which RGC axons make subtle but significant mistakes during their intraretinal growth and inappropriately defasciculate along their pathway. The distribution of Sfrp1 and Sfrp2 in the eye is consistent with the idea that Sfrp1/2 normally constrain axon growth into the fiber layer and the optic disc. Disheveled axon growth instead seems linked to Sfrp-mediated modulation of metalloproteinase activity. Indeed, retinal explants from embryos with different Sfrp-null alleles or explants overexpressing ADAM10 extend axons with a disheveled appearance, which is reverted by the addition of Sfrp1 or an ADAM10-specific inhibitor. This mode of growth is associated with an abnormal proteolytic processing of L1 and N-cadherin, two ADAM10 substrates previously implicated in axon guidance. We thus propose that Sfrps contribute to coordinate visual axon growth with a dual mechanism: by directly signaling at the growth cone and by regulating the processing of other relevant cues.
Assuntos
Axônios/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Proteínas de Membrana/fisiologia , Células Ganglionares da Retina/fisiologia , Vias Visuais/embriologia , Vias Visuais/crescimento & desenvolvimento , Animais , Feminino , Receptores Frizzled/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos TransgênicosRESUMO
The Sox2 transcription factor is active in stem/progenitor cells throughout the developing vertebrate central nervous system. However, its conditional deletion at E12.5 in mouse causes few brain developmental problems, with the exception of the postnatal loss of the hippocampal radial glia stem cells and the dentate gyrus. We deleted Sox2 at E9.5 in the telencephalon, using a Bf1-Cre transgene. We observed embryonic brain defects that were particularly severe in the ventral, as opposed to the dorsal, telencephalon. Important tissue loss, including the medial ganglionic eminence (MGE), was detected at E12.5, causing the subsequent impairment of MGE-derived neurons. The defect was preceded by loss of expression of the essential ventral determinants Nkx2.1 and Shh, and accompanied by ventral spread of dorsal markers. This phenotype is reminiscent of that of mice mutant for the transcription factor Nkx2.1 or for the Shh receptor Smo. Nkx2.1 is known to mediate the initial activation of ventral telencephalic Shh expression. A partial rescue of the normal phenotype at E14.5 was obtained by administration of a Shh agonist. Experiments in Medaka fish indicate that expression of Nkx2.1 is regulated by Sox2 in this species also. We propose that Sox2 contributes to Nkx2.1 expression in early mouse development, thus participating in the region-specific activation of Shh, thereby mediating ventral telencephalic patterning induction.
Assuntos
Padronização Corporal/genética , Desenvolvimento Embrionário/genética , Proteínas Hedgehog/genética , Proteínas Nucleares/genética , Fatores de Transcrição SOXB1/fisiologia , Telencéfalo/embriologia , Fatores de Transcrição/genética , Animais , Células Cultivadas , Embrião de Mamíferos , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Hedgehog/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Nucleares/metabolismo , Gravidez , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismo , Telencéfalo/metabolismo , Fator Nuclear 1 de Tireoide , Fatores de Transcrição/metabolismo , Ativação Transcricional/genéticaRESUMO
Sonic Hedgehog (Shh) signaling is an important determinant of vertebrate retinal ganglion cell (RGC) development. In mice, there are two major RGC populations: (1) the Islet2-expressing contralateral projecting (c)RGCs, which both produce and respond to Shh; and (2) the Zic2-expressing ipsilateral projecting RGCs (iRGCs), which lack Shh expression. In contrast to cRGCs, iRGCs, which are generated in the ventrotemporal crescent (VTC) of the retina, specifically express Boc, a cell adhesion molecule that acts as a high-affinity receptor for Shh. In Boc(-/-) mutant mice, the ipsilateral projection is significantly decreased. Here, we demonstrate that this phenotype results, at least in part, from the misspecification of a proportion of iRGCs. In Boc(-/-) VTC, the number of Zic2-positive RGCs is reduced, whereas more Islet2/Shh-positive RGCs are observed, a phenotype also detected in Zic2 and Foxd1 null embryos. Consistent with this observation, organization of retinal projections at the dorsal lateral geniculate nucleus is altered in Boc(-/-) mice. Analyses of the molecular and cellular consequences of introducing Shh into the developing VTC and Zic2 and Boc into the central retina indicate that Boc expression alone is insufficient to fully activate the ipsilateral program and that Zic2 regulates Shh expression. Taking these data together, we propose that expression of Boc in cells from the VTC is required to sustain Zic2 expression, likely by regulating the levels of Shh signaling from the nearby cRGCs. Zic2, in turn, directly or indirectly, counteracts Shh and Islet2 expression in the VTC and activates the ipsilateral program.
Assuntos
Lateralidade Funcional/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/genética , Proteínas Hedgehog/metabolismo , Imunoglobulina G/metabolismo , Receptores de Superfície Celular/metabolismo , Células Ganglionares da Retina/fisiologia , Transdução de Sinais/fisiologia , Animais , Eletroporação , Retroalimentação Fisiológica/fisiologia , Fatores de Transcrição Forkhead/deficiência , Lateralidade Funcional/genética , Corpos Geniculados/fisiologia , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Imunoglobulina G/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores de Superfície Celular/genética , Retina/citologia , Transdução de Sinais/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Vias Visuais/fisiologiaRESUMO
INTRODUCTION: Aesthetic medicine is characterized by the efficacy and safety of treatments. Although sometimes adverse events could be occurred, in this case vascular occlusion is the most serious of them. The tissue is deprived of oxygen and there is a possibility of necrosis, so it is necessary to remove the tissue filler and promote oxygenation. OBJECTIVE: We propose the hyperbaric oxygenation treatment to oxygenate the tissue after vascular occlusion generated by a tissue filler such as Hyaluronic Acid. RESULTS: We show how hyperbaric oxygenation treatment is an adjuvant therapy after vascular occlusion, improving tissue regeneration and prevent or limit scars or sequelae. CONCLUSION: Hyperbaric oxygenation treatment is a safe and effective method to treat vascular accident, improving tissue oxygenation in early cases and improving tissue regeneration in cases with necrosis.
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Preenchedores Dérmicos , Oxigenoterapia Hiperbárica , Humanos , Oxigenoterapia Hiperbárica/efeitos adversos , Cicatrização , Ácido Hialurônico/efeitos adversos , Cicatriz/etiologia , Necrose/induzido quimicamente , Preenchedores Dérmicos/efeitos adversosRESUMO
Purpose: Obesity is a multifactorial condition with a relevant genetic correlation. Recent advances in genomic research have identified several single nucleotide polymorphisms (SNPs) in genes such as FTO, MCM6, HLA, and MC4R, associated with obesity. This study aimed to evaluate the association of 102 SNPs with BMI and weight loss treatment response in a multi-ethnic population. Methods: The study analyzed 9,372 patients for the correlation between SNPs and BMI (dataset A). The correlation between SNP and weight loss was accessed in 474 patients undergoing different treatments (dataset B). Patients in dataset B were further divided into 3 categories based on the type of intervention: dietary therapy, intragastric balloon procedures, or surgeries. SNP association analysis and multiple models of inheritance were performed. Results: In dataset A, ten SNPs, including rs9939609 (FTO), rs4988235 (MCM6), and rs2395182 (HLA), were significantly associated with increased BMI. Additionally, other four SNPs, rs7903146 (TCF7L2), (rs6511720), rs5400 (SLC2A2), and rs7498665 (SH2B1), showed sex-specific correlation. For dataset B, SNPs rs2016520 (PPAR-Delta) and rs2419621 (ACSL5) demonstrated significant correlation with weight loss for all treatment types. In patients who adhered to dietary therapy, SNPs rs6544713 (ABCG8) and rs762551 (CYP1A2) were strongly correlated with weight loss. Patients undergoing surgical or endoscopic procedures exhibited differential correlations with several SNPs, including rs1801725 (CASR) and rs12970134 (MC4R), and weight loss. Conclusion: This study provides valuable insights into the genetic factors influencing BMI and weight loss response to different treatments. The findings highlight the potential for personalized weight management approaches based on individual genetic profiles.
RESUMO
INTRODUCTION: Hyaluronic acid is a safe dermal filler, but sometimes late granuloma is generated. This adverse effect is an inflammatory process, and its causes are not clear. Late granuloma generation could be due to the reaction to residual components of the bacterial wall present into hyaluronic acid, such as lipoteichoic acid (LTA). Other possibility is hyaluronic acid degraded could be trigger this inflammatory reaction. OBJECTIVE: Study possible molecular mechanism that could be implicated into the late granuloma formation. We wonder whereas inflammatory response activation is triggered by lower molecular weight hyaluronic acid or Gram-positive bacterial components as LTA. METHODS: We analyzed one adverse case generated by hyaluronic acid injections. Our study with one nodule through chemical and immunofluorescence histologic technics. RESULTS: In this case, observe a late granuloma without infectious process. Histological analysis shown few large Langerhans cells around fillers and multiple immunological cells infiltrated. Immunofluorescent study shown immunological cells (CD45 positives cells) with high TLR2 expression (hyaluronic acid and LTA receptor). LIMITATIONS: The difficulty of obtaining biopsy samples of nodules implies that the number of cases analyzed is very low. CONCLUSION: New model is proposed in which weight of hyaluronic acid and LTA could be able to trigger inflammation. This process could be mediated by TLR2 expressed in infiltrated immune cells.
Assuntos
Preenchedores Dérmicos , Ácido Hialurônico , Humanos , Ácido Hialurônico/efeitos adversos , Receptor 2 Toll-Like , Peso Molecular , Inflamação/induzido quimicamente , Granuloma/induzido quimicamente , Preenchedores Dérmicos/efeitos adversosRESUMO
Reg-1α belongs to the Reg family of small, secreted proteins expressed in both pancreas and nervous system. Reg-1α is composed of two domains, an insoluble C-type lectin domain and a short soluble N-terminal peptide, which is released from the molecule upon proteolytic N-terminal processing, although the biological significance of this proteolysis remains unclear. We have previously shown that binding of Reg-1α to its receptor Extl3 stimulates axonal outgrowth. Reg-1α and Extl3 genes are expressed in the developing cortex but their expression decreases in adulthood, pointing to a possible function of this signaling system at the early developmental stages. Here, we demonstrate that recombinant Reg-1α increases migration and differentiation of cultured embryonic rat telencephalic progenitors via the activation of GSK-3ß activity. In vivo overexpression of Reg-1α by in utero electroporation, has a similar effect, favoring premature differentiation of cortical progenitors. Notably, the N-terminal soluble domain, but not the C-type lectin domain, is largely responsible for Reg-1α effects on cortical neuronal differentiation. We thus conclude that Reg-1α via its proteolytically generated N-terminal domain is required for basic development processes.
RESUMO
A prevalent developmental mechanism for the assignment of cell identities is the production of spatiotemporal concentration gradients of extracellular signaling molecules that are interpreted by the responding cells. One of such signaling systems is the Shh gradient that controls neuronal subtype identity in the ventral spinal cord. Using loss and gain of function approaches in chick and mouse embryos, we show here that the fibroblast growth factor (FGF) signaling pathway is required to restrict the domains of ventral gene expression as neuroepithelial cells become exposed to Shh during caudal extension of the embryo. FGF signaling activates the expression of the Shh receptor and negative pathway regulator Patched 2 (Ptch2) and therefore can enhance a negative feedback loop that restrains the activity of the pathway. Thus, we identify one of the mechanisms by which FGF signaling acts as a modulator of the onset of Shh signaling activity in the context of coordination of ventral patterning and caudal axis extension. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 956-971, 2016.
Assuntos
Fatores de Crescimento de Fibroblastos/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Proteínas Hedgehog/fisiologia , Transdução de Sinais/fisiologia , Corno Ventral da Medula Espinal/fisiologia , Animais , Embrião de Galinha , Humanos , Camundongos , Corno Ventral da Medula Espinal/embriologiaRESUMO
Cdon and Boc, and their Drosophila homologues Ihog and Boi, are evolutionary conserved transmembrane glycoproteins belonging to a subgroup of the Immunoglobulin superfamily of cell adhesion molecules (CAMs). Initially isolated in vertebrates as CAMs that link cadherin function with MAPK signaling in myoblast differentiation, they have thereafter been shown to act as essential receptors for the Hedgehog (Hh) family of secreted proteins. They associate with both ligand and other Hh receptor components, including Ptch and Gas1, thus forming homo- and heteromeric complexes. In Drosophila, they are also involved in ligand processing and release from Hh producing cells. Cdon/Boc and Ihog/Boi can substitute one another and play redundant functions is some contexts. In addition, Boc, but not Cdon, mediates axon guidance information provided by Hh in specific neuronal populations, whereas mutations in the CDON cause holoprosencephaly, a human congenital anomaly defined by forebrain midline defects prominently associated with diminished Hh pathway activity.