RESUMO
Mutations in the retinoblastoma tumor suppressor gene (rb1) cause both sporadic and familial forms of childhood retinoblastoma. Despite its clinical relevance, the roles of rb1 during normal retinotectal development and function are not well understood. We have identified mutations in the zebrafish space cadet locus that lead to a premature truncation of the rb1 gene, identical to known mutations in sporadic and familial forms of retinoblastoma. In wild-type embryos, axons of early born retinal ganglion cells (RGC) pioneer the retinotectal tract to guide later born RGC axons. In rb1 deficient embryos, these early born RGCs show a delay in cell cycle exit, causing a transient deficit of differentiated RGCs. As a result, later born mutant RGC axons initially fail to exit the retina, resulting in optic nerve hypoplasia. A significant fraction of mutant RGC axons eventually exit the retina, but then frequently project to the incorrect optic tectum. Although rb1 mutants eventually establish basic retinotectal connectivity, behavioral analysis reveals that mutants exhibit deficits in distinct, visually guided behaviors. Thus, our analysis of zebrafish rb1 mutants reveals a previously unknown yet critical role for rb1 during retinotectal tract development and visual function.
Assuntos
Retina , Proteína do Retinoblastoma/genética , Retinoblastoma/genética , Peixe-Zebra , Animais , Axônios/metabolismo , Axônios/patologia , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Mutação , Retina/citologia , Retina/crescimento & desenvolvimento , Retina/metabolismo , Células Ganglionares da Retina/citologia , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/fisiologia , Retinoblastoma/patologia , Proteína do Retinoblastoma/metabolismo , Colículos Superiores/citologia , Colículos Superiores/metabolismoRESUMO
Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a natural polyphenolic compound that exists in Polygonum cuspidatum, grapes, peanuts and berries, as well as their manufactured products, especially red wine. Resveratrol is a pharmacologically active compound that interacts with multiple targets in a variety of cardiovascular disease models to exert protective effects or induce a reduction in cardiovascular risks parameters. This review attempts to primarily serve to summarize the current research findings regarding the putative cardioprotective effects of resveratrol and the molecular pathways underlying these effects. One intent is to hopefully provide a relatively comprehensive resource for clues that may prompt ideas for additional mechanistic studies which might further elucidate and strengthen the role of the stilbene family of compounds in cardiovascular disease and cardioprotection. Model systems that incorporate a significant functional association with tissues outside of the cardiovascular system proper, such as adipose (cell culture, obesity models) and pancreatic (diabetes) tissues, were reviewed, and the molecular pathways and/or targets related to these models and influenced by resveratrol are discussed. Because the body of work encompassing the stilbenes and other phytochemicals in the context of longevity and the ability to presumably mitigate a plethora of afflictions is replete with conflicting information and controversy, especially so with respect to the human response, we tried to remain as neutral as possible in compiling and presenting the more current data with minimal commentary, permitting the reader free reign to extract the knowledge most helpful to their own investigations.
Assuntos
Cardiotônicos/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Estilbenos/uso terapêutico , Animais , Cardiotônicos/farmacologia , Humanos , Resveratrol , Estilbenos/farmacologiaRESUMO
Retinal ganglion cell axons exit the eye, enter the optic stalk, cross the ventral midline at the optic chiasm, and terminate in the optic tectum of the zebrafish. While in the optic stalk, they grow immediately adjacent to cells expressing the powerful retinal axon repellent slit2. The chemokine stromal cell-derived factor-1 (SDF1) is expressed within the optic stalk and its receptor CXCR4 is expressed in retinal ganglion cells. SDF1 makes cultured retinal axons less responsive to slit2. Here, we show that reducing SDF1 signaling in vivo rescues retinal axon pathfinding errors in zebrafish mutants that have a partial functional loss of the slit receptor robo2. In contrast, reducing SDF1 signaling in animals that completely lack the robo2 receptor does not rescue retinal guidance errors. These results demonstrate that endogenous levels of SDF1 antagonize the repellent effects of slit/robo signaling in vivo and that this antagonism is important during axonal pathfinding.
Assuntos
Quimiocinas CXC/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Receptores Imunológicos/antagonistas & inibidores , Transdução de Sinais/fisiologia , Proteínas de Peixe-Zebra/fisiologia , Animais , Células Cultivadas , Quimiocina CXCL12 , Quimiocinas CXC/genética , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Receptores CXCR4/biossíntese , Receptores CXCR4/genética , Receptores Imunológicos/biossíntese , Receptores Imunológicos/genética , Células Ganglionares da Retina/metabolismo , Peixe-Zebra , Proteínas de Peixe-Zebra/antagonistas & inibidores , Proteínas de Peixe-Zebra/biossíntese , Proteínas de Peixe-Zebra/genéticaRESUMO
The transcription factors of the Sox family play important roles in diverse developmental processes. A number of genetic studies have established that Sox10 is a major regulator of neural crest formation. Here, we report the cloning and functional analysis of the Xenopus Sox10 gene. Sox10 mRNA accumulates during gastrulation at the lateral edges of the neural plate, in the neural crest-forming region. In this tissue, Sox10 expression is regulated by Wnt signaling and colocalizes with two major regulators of neural crest formation, Slug and Sox9. While initially expressed in neural crest cells from all axial levels, at the tailbud stage, Sox10 is downregulated in the cranial neural crest and persists mostly in neural crest cells from the trunk region. Overexpression of Sox10 causes a dramatic expansion of the Slug expression domain. We show that the C-terminal portion of Sox10 is sufficient to mediate this activity. Later during embryogenesis, Sox10-injected embryos show a massive increase in pigment cells (Trp-2-expressing cells). The responsiveness of the embryo to Sox10 overexpression by expansion of the Slug expression domain and ectopic production of Trp-2-positive cells and differentiated melanocytes is lost during gastrulation, as revealed by a hormone-inducible Sox10 construct. These results suggest that Sox10 is involved in the specification of neural crest progenitors fated to form the pigment cell lineage.