BMP4-dependent expression of Xenopus Grainyhead-like 1 is essential for epidermal differentiation
Jianning TaoEmin KuliyevXi WangXiuling LiTomasz WilanowskiStephen M. JanePaul E. MeadJohn M. Cunningham
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Morphogen-dependent epidermal-specific transacting factors have not been defined in vertebrates. We demonstrate that a member of the grainyhead transcription factor family, Grainyhead-like 1 (XGrhl1) is essential for ectodermal ontogeny in Xenopus laevis. Expression of this factor is restricted to epidermal cells. Moreover, XGrhl1 is regulated by the BMP4 signaling cascade. Disruption of XGrhl1 activity in vivo results in a severe defect in terminal epidermal differentiation, with inhibition of XK81A1 epidermal keratin gene expression, a key target of BMP4 signaling. Furthermore, transcription of the XK81A1 gene is modulated directly by binding of XGRHL1 to a promoter-localized binding motif that is essential for high-level expression. These results establish a novel developmental role for XGrhl1 as a crucial tissue-specific regulator of vertebrate epidermal differentiation.Keywords:
Morphogen
During development of multicellular organisms, morphogen is a kind of signaling molecules produced at a local region and transported into a development field, which acts as dose-dependent regulators of gene expression, directs and controls cellular differentiation. Some experiments showed that during embryo development, dynamical processes of morphogen transport always accompany the tissue growth. However, how tissue growth affects morphogen gradients remains to be explored. To answer this problem, we propose a reaction-diffusion-convection model for morphogen transport. For this model, we mainly investigate local accumulation times (LATs) of morphogen gradients, which are a measure for time of forming the steady state of morphogen gradients. In this paper, we simplify the method of calculating the LATs and use this method to obtain analytic expressions of the LATs for uniform and linear growth, respectively. Besides, for tissue nonuniform growth, we apply an approximation method of the LATs to study them. This paper shows that tissue growth can shorten the LATs of morphogen gradients.
Morphogen
Multicellular organism
Concentration gradient
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Morphogens are factors that influence the development of cells into organized clusters or patterns. Cells can detect their position in gradients of morphogen concentration within the broader context of surrounding cells and differentiate appropriately. Gurdon and Bourillot review the ways in which cells perceive and interpret morphogen gradients. Essential to the cell response is whether the concentration of a morphogen has reached a critical threshold and whether the cell has the appropriate signaling proteins (in appropriate amounts) to respond to the morphogen by differentiating. The authors also raise the intriguing question of how cells respond when the morphogen gradients themselves change over time.J. B. Gurdon, P.-Y. Bourillot, Morphogen gradient interpretation. Nature 413, 797-803, (2001). [Online Journal]
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The differentiation of murine erythroleukemia cells and the expression of SCL, Id1 and c-myc regulatory genes were studied. The first gene is a positive regulator of differentiation, while the other two are both negative regulators of differentiation and positive regulators of proliferation. Accordingly, our data show that when differentiation is stimulated SCL is upregulated while Id1 and c-myc are, coordinately, downregulated. The cultures were treated with two adenosine derivatives, 3-deazaadenosine and 3-deazaaristeromycin, known to act on the metabolic pathway of the methyl donor S-adenosylmethionin, in order to assess the possibility of a coordinated modulation, by these drugs, of regulatory gene expression and erythroid cell differentiation. 3-Deazaaristeromycin caused the simultaneous downregulation of Id1 and c-myc, whereas 3-deazaadenosine caused their upregulation; both drugs produced a transient increase in SCL expression. The use of these drugs evidenced a predominant regulatory effect of negative regulators in the control of erythroid differentiation. The distinct effects of the two drugs on regulatory gene expression led to an increased differentiation induced by 3-deazaaristeromycin and to a reduced differentiation induced by 3-deazaadenosine, if compared with controls. Southern analysis of DNA digested with methylation-specific restriction endonucleases showed that the administration of 3-deazaaristeromycin resulted in hypomethylation of SCL and c-myc, thus evidencing, in these cells, a clear correlation between DNA hypomethylation and differentiation but no straightforward correlation between DNA methylation and gene expression. J. Cell. Biochem. 81:401–412, 2001. © 2001 Wiley-Liss, Inc.
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Naama Barkai1,2 and Ben-Zion Shilo1 Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel Physics of Complex Systems, Weizmann Institute of Science, Rehovot 76100, Israel Correspondence: naama.barkai{at}weizmann.ac.il
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The differentiation of murine erythroleukemia cells and the expression of SCL, Id1 and c-myc regulatory genes were studied. The first gene is a positive regulator of differentiation, while the other two are both negative regulators of differentiation and positive regulators of proliferation. Accordingly, our data show that when differentiation is stimulated SCL is upregulated while Id1 and c-myc are, coordinately, downregulated. The cultures were treated with two adenosine derivatives, 3-deazaadenosine and 3-deazaaristeromycin, known to act on the metabolic pathway of the methyl donor S-adenosylmethionin, in order to assess the possibility of a coordinated modulation, by these drugs, of regulatory gene expression and erythroid cell differentiation. 3-Deazaaristeromycin caused the simultaneous downregulation of Id1 and c-myc, whereas 3-deazaadenosine caused their upregulation; both drugs produced a transient increase in SCL expression. The use of these drugs evidenced a predominant regulatory effect of negative regulators in the control of erythroid differentiation. The distinct effects of the two drugs on regulatory gene expression led to an increased differentiation induced by 3-deazaaristeromycin and to a reduced differentiation induced by 3-deazaadenosine, if compared with controls. Southern analysis of DNA digested with methylation-specific restriction endonucleases showed that the administration of 3-deazaaristeromycin resulted in hypomethylation of SCL and c-myc, thus evidencing, in these cells, a clear correlation between DNA hypomethylation and differentiation but no straightforward correlation between DNA methylation and gene expression.
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Morphogens are factors that influence the development of cells into organized clusters or patterns. Cells can detect their position in gradients of morphogen concentration within the broader context of surrounding cells and differentiate appropriately. Gurdon and Bourillot review the ways in which cells perceive and interpret morphogen gradients. Essential to the cell response is whether the concentration of a morphogen has reached a critical threshold and whether the cell has the appropriate signaling proteins (in appropriate amounts) to respond to the morphogen by differentiating. The authors also raise the intriguing question of how cells respond when the morphogen gradients themselves change over time. J. B. Gurdon, P.-Y. Bourillot, Morphogen gradient interpretation. Nature 413 , 797-803, (2001). [Online Journal]
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Cells at different positions in a developing tissue receive different concentrations of signaling molecules, called morphogens, and this influences their cell fate. Morphogen concentration gradients have been proposed to control patterning as well as growth in many developing tissues. Some outstanding questions about tissue patterning by morphogen gradients are the following: What are the mechanisms that regulate gradient formation and shape? Is the positional information encoded in the gradient sufficiently precise to determine the positions of target gene domain boundaries? What are the temporal dynamics of gradients and how do they relate to patterning and growth? These questions are inherently quantitative in nature and addressing them requires measuring morphogen concentrations in cells, levels of downstream signaling activity, and kinetics of morphogen transport. Here we first present methods for quantifying morphogen gradient shape in which the measurements can be calibrated to reflect actual morphogen concentrations. We then discuss using fluorescence recovery after photobleaching to study the kinetics of morphogen transport at the tissue level. Finally, we present particle tracking as a method to study morphogen intracellular trafficking.
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Photobleaching
Developmental Biology
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Morphogens are long-range signaling molecules that pattern developing tissues in a concentration-dependent manner. The graded activity of morphogens within tissues exposes cells to different signal levels and leads to region-specific transcriptional responses and cell fates. In its simplest incarnation, a morphogen signal forms a gradient by diffusion from a local source and clearance in surrounding tissues. Responding cells often transduce morphogen levels in a linear fashion, which results in the graded activation of transcriptional effectors. The concentration-dependent expression of morphogen target genes is achieved by their different binding affinities for transcriptional effectors as well as inputs from other transcriptional regulators. Morphogen distribution and interpretation are the result of complex interactions between the morphogen and responding tissues. The response to a morphogen is dependent not simply on morphogen concentration but also on the duration of morphogen exposure and the state of the target cells. In this review, we describe the morphogen concept and discuss the mechanisms that underlie the generation, modulation, and interpretation of morphogen gradients.
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