Showing papers on "Morphogen published in 1991"
TL;DR: The results demonstrate that HGF, a polypeptide that was identified as a mitogen for cultured hepatocytes, has the properties of a paracrine mediator of epithelial morphogenesis, and suggest that it may play important roles in the formation of parenchymal organs during embryonic development.
1,182 citations
TL;DR: The chicken Hox-4 homeogenes, like those of the mouse, are coordinately expressed in partially overlapping domains during wing development and the mirror-image patterns of H Cox-4 gene expression correlate with the subsequent development of mirror- image patterns of digits.
Abstract: The chicken Hox-4 homeogenes, like those of the mouse, are coordinately expressed in partially overlapping domains during wing development. Local application of retinoic acid, a putative endogenous morphogen, induces de novo transcription of Hox-4 genes. The mirror-image patterns of Hox-4 gene expression, which are obtained in this way, correlate with the subsequent development of mirror-image patterns of digits. Hox-4 genes probably encode positional information.
395 citations
TL;DR: It is argued that nos acts as a morphogen, controlling hb expression (and hence abdominal pattern) as a function of its concentration-dependent interaction with the NREs, both necessary and sufficient to confer nos-dependent regulation.
390 citations
TL;DR: The dorsal blastopore lip of the early Xenopus laevis gastrula can organize a complete secondary body axis when transplanted to another embryo and the identification of four types of complementary DNAs from homeobox-containing genes that fulfill this criterion.
Abstract: The dorsal blastopore lip of the early Xenopus laevis gastrula can organize a complete secondary body axis when transplanted to another embryo A search for potential gene regulatory components specifically expressed in the organizer was undertaken that resulted in the identification of four types of complementary DNAs from homeobox-containing genes that fulfill this criterion The most abundant of these encodes a DNA-binding specificity similar to that of the Drosophila melanogaster anterior morphogen bicoid The other three are also homologous to developmentally significant Drosophila genes These four genes may participate in the regulation of the developmental potential of the organizer
346 citations
TL;DR: Using a combination of promoter fusion-P-transformation assays, and in vitro DNA-binding assays coupled with site-directed mutagenesis, a direct link between dl-binding sites and twi expression in the early embryo is established.
Abstract: A gradient of the maternal morphogen dorsal (dl) initiates the differentiation of various tissues along the dorsal-ventral axis of early Drosophila embryos. dl is a sequence-specific DNA-binding protein that is related to the mammalian regulatory factor NF-kappa B. Previous studies suggest that dl can function as a transcriptional repressor. To determine how dl functions as an activator we have examined the promoter of the mesoderm determinant gene twist (twi). Genetic studies suggest that peak levels of dl protein in ventral regions of early embryos initiate twi expression. Using a combination of promoter fusion-P-transformation assays, and in vitro DNA-binding assays coupled with site-directed mutagenesis, we establish a direct link between dl-binding sites and twi expression in the early embryo. We also present evidence that the dorsal-ventral limits of twi expression depend on the number and affinity of dl-binding sites present in its promoter. A comparison of twi with a second dl target gene, zen, suggests a correlation between the affinities of dl-binding sites and response to different thresholds of dl morphogen.
346 citations
TL;DR: These experiments suggest that repression involves a competition or short-range quenching mechanism, whereby the binding of gt and Kr interferes with the binding or activity of bcd and hb activators at overlapping or neighboring sites within the eve stripe 2 promoter element.
Abstract: The periodic, seven-stripe pattern of the primary pair-rule gene even-skipped (eve) is initiated by crude, overlapping gradients of maternal and gap gene proteins in the early Drosophila embryo. Previous genetic studies suggest that one of the stripes, stripe 2, is initiated by the maternal morphogen bicoid (bcd) and the gap protein hunchback (hb), while the borders of the stripe are formed by selective repression, involving the gap protein giant (gt) in anterior regions and the Kruppel (Kr) protein in posterior regions. Here, we present several lines of evidence that are consistent with this model for stripe 2 expression, including in vitro DNA-binding experiments and transient cotransfection assays in cultured cells. These experiments suggest that repression involves a competition or short-range quenching mechanism, whereby the binding of gt and Kr interferes with the binding or activity of bcd and hb activators at overlapping or neighboring sites within the eve stripe 2 promoter element. Such short-range repression could reflect a general property of promoters composed of multiple, but autonomous regulatory elements.
339 citations
TL;DR: A direct link is established between binding sites for these regulatory proteins in the stripe 2 promoter element and the expression of the stripe during early embryogenesis.
Abstract: Gene expression stripes in Drosophila melanogaster embryos provide a model for how eukaryotic promoters are turned on and off in response to combinations of transcriptional regulators. Genetic studies suggested that even-skipped (eve) stripe 2 is controlled by three gap genes, hunchback (hb), Kruppel (Kr), and giant (gt), and by the maternal morphogen bicoid (bcd). A direct link is established between binding sites for these regulatory proteins in the stripe 2 promoter element and the expression of the stripe during early embryogenesis. The bcd and hb protein binding sites mediate activation, whereas neighboring gt and Kr protein sites repress expression and establish the stripe borders. The stripe 2 element has the properties of a genetic on-off switch.
328 citations
TL;DR: In this paper, the cytoskeletal requirements for bicoid (bcd) RNA localization during Drosophila oogenesis were examined, and it was shown that the localization machinery is a component of the cortical cytoskeleton.
Abstract: We have examined cytoskeletal requirements for bicoid (bcd) RNA localization during Drosophila oogenesis. bcd is an anterior morphogen whose proper function relies on the localization of its messenger RNA to the anterior cortex of the egg. Drugs that depolymerize microtubules perturb all aspects of bcd RNA localization. During recovery from drug treatment, bcd RNA relocalizes to the oocyte cortex, suggesting that the localization machinery is a component of the cortical cytoskeleton. Taxol, a drug that stabilizes microtubules, also effectively disrupts bcd RNA localization, and the effects of taxol treatments on exuperantia and swallow mutants suggest general roles for these gene products in the multi-step bcd RNA localization process.
310 citations
TL;DR: It is found that when the bead containing either retinoic acid or an analogue but not the ZPA, was implanted in the anterior margin of the chick limb bud, expression of the retinosic acid receptor type-β gene was induced around the bead within 4 h, indicating that the primary function of exogenous retinoIC acid is to induce polarizing activity in the limb bud.
Abstract: Retinoic acid is a putative morphogen in limb formation in the chick and other vertebrates. In chick limb formation, it is thought that retinoic acid is released from the zone of polarizing activity (ZPA) and the concentration gradient of retinoic acid formed from the posterior to the anterior provides positional cues for digit formation. Implantation of a bead containing retinoic acid at the anterior margin of the limb bud induces a mirror-image symmetrical duplication of the digit pattern similar to that observed when the ZPA is grafted into the anterior margin of the host limb bud. Also, the level of endogenous retinoic acid (25 nM on average) is higher in the posterior one third of the limb bud. We found that when the bead containing either retinoic acid or an analogue but not the ZPA, was implanted in the anterior margin of the chick limb bud, expression of the retinoic acid receptor type-beta gene was induced around the bead within 4 h. These results indicate that exogenous retinoic acid is not identical with the ZPA morphogen. As the anterior tissue exposed to retinoic acid has polarizing activity, we conclude that the primary function of exogenous retinoic acid is to induce polarizing activity in the limb bud.
249 citations
TL;DR: Two of the genes, dpp and twi, are unaffected by mutations in any of the tested zygotic dorsal-ventral genes, suggesting that dppand twi are the primary patterning genes for dorsal ectoderm and mesoderm, respectively.
Abstract: We have analyzed the contributions made by maternal and zygotic genes to the establishment of the expression patterns of four zygotic patterning genes: decapentaplegic (dpp), zerknullt (zen), twist (twi), and snail (sna). All of these genes are initially expressed either dorsally or ventrally in the segmented region of the embryo, and at the poles. In the segmented region of the embryo, correct expression of these genes depends on cues from the maternal morphogen dorsal (dl). The dl gradient appears to be interpreted on three levels: dorsal cells express dpp and zen, but not twi and sna; lateral cells lack expression of all four genes; ventral cells express twi and sna, but not dpp and zen. dl appears to activate the expression of twi and sna and repress the expression of dpp and zen. Polar expression of dpp and zen requires the terminal system to override the repression by dl, while that of twi and sna requires the terminal system to augment activation by dl. The zygotic expression patterns established by the maternal genes appear to specify autonomous domains that carry out independent developmental programs, insofar as mutations in the genes that are expressed ventrally do not affect the initiation or ontogeny of the expression patterns of the genes that are expressed dorsally, and vice versa. However, interactions between the zygotic genes specific to a particular morphological domain appear to be important for further elaboration of the three levels specified by dl. Two of the genes, dpp and twi, are unaffected by mutations in any of the tested zygotic dorsal-ventral genes, suggesting that dpp and twi are the primary patterning genes for dorsal ectoderm and mesoderm, respectively.
248 citations
TL;DR: The formation of the sharp snail border involves dosage-sensitive interactions between dorsal and twist, which encode regulatory proteins that are related to the mammalian transcription factors NF-kB and MyoD, respectively.
Abstract: A gradient of the maternal morphogen dorsal establishes asymmetric patterns of gene expression along the dorsal-ventral axis of early embryos and activates the regulatory genes twist and snail, which are responsible for the differentiation of the ventral mesoderm. Expression of snail is restricted to the presumptive mesoderm, and the sharp lateral limits of this expression help to define the mesoderm-neuroectoderm boundary by repressing the expression of regulatory genes that are responsible for the differentiation of the neuroectoderm. The snail gene encodes a zinc finger protein, and neuroectodermal genes that are normally restricted to ventral-lateral regions of early embryos are expressed throughout ventral regions of snail- mutants. The formation of the sharp snail border involves dosage-sensitive interactions between dorsal and twist, which encode regulatory proteins that are related to the mammalian transcription factors NF-kB and MyoD, respectively.
TL;DR: The results suggest that positional information assigned by a ZPA morphogen is imprinted on cellular memory by expression of the Chox-4 genes to maintain positional signaling along the anteroposterior axis in the limb field.
TL;DR: It is demonstrated that dorsal is a sequence-specific DNA-binding protein that recognizes a motif similar to that recognized by the mammalian transcriptional activator NF-kappa B.
TL;DR: It is shown that dl is a DNA-binding protein that specifically interacts with distal sequences of the zerknüllt (zen) promoter, one of the genetic targets of the morphogen.
TL;DR: It is shown that in contrast to the dorsal group genes, the maternal gene cactus acts as a negative regulator of the nuclear localization of the dorsal protein, and the inhibitory function that cactus product exerts on the nuclear transport ofThe dorsal protein appears to be antagonized on the ventral side.
Abstract: The dorsoventral pattern of the Drosophila embryo is mediated by a gradient of nuclear localization of the dorsal protein which acts as a morphogen. Establishment of the nuclear concentration gradient of dorsal protein requires the activities of the 10 maternal ‘dorsal group’ genes whose function results in the positive regulation of the nuclear uptake of the dorsal protein. Here we show that in contrast to the dorsal group genes, the maternal gene cactus acts as a negative regulator of the nuclear localization of the dorsal protein. While loss of function mutations of any of the dorsal group genes lead to dorsalized embryos, loss of cactus function results in a ventralization of the body pattern. Progressive loss of maternal cactus activity causes progressive loss of dorsal pattern elements accompanied by the expansion of ventrolateral and ventral anlagen. However, embryos still retain dorsoventral polarity, even if derived from germline clones using the strongest available, zygotic lethal cactus alleles. In contrast to the loss-of-function alleles, gain-of-function alleles of cactus cause a dorsalization of the embryonic pattern. Genetic studies indicate that they are not overproducers of normal activity, but rather synthesize products with altered function. Epistatic relationships of cactus with dorsal group genes were investigated by double mutant analysis. The dorsalized phenotype of the dorsal mutation is unchanged upon loss of cactus activity. This result implies that cactus acts via dorsal and has no independent morphogen function. In all other dorsal group mutant backgrounds, reduction of cactus function leads to embryos that express ventrolateral pattern elements and have increased nuclear uptake of the dorsal protein at all positions along the dorsoventral axis. Thus, the cactus gene product can prevent nuclear transport of dorsal protein in the absence of function of the dorsal group genes. Genetic and cytoplasmic transplantation studies suggest that the cactus product is evenly distributed along the dorsoventral axis. Thus the inhibitory function that cactus product exerts on the nuclear transport of the dorsal protein appears to be antagonized on the ventral side. We discuss models of how the action of the dorsal group genes might counteract the cactus function ventrally.
TL;DR: Gt is a bona fide gap gene, which acts with hb, Krüppel and kni to initiate striped patterns of gene expression in the early embryo, and evidence that different concentrations of hb protein are instructive in defining the limits of kni and gt expression within the presumptive abdomen is presented.
Abstract: We describe the regulated expression of the segmentation gene giant (gt) during early embryogenesis. The gt protein is expressed in two broad gradients in precellular embryos, one in anterior regions and the other in posterior regions. Double immunolocalization studies show that the gt patterns overlap with protein gradients specified by the gap genes hunchback (hb) and knirps (kni). Analysis of all known gap mutants, as well as mutations that disrupt each of the maternal organizing centers, indicate that maternal factors are responsible for initiating gt expression, while gap genes participate in the subsequent refinement of the pattern. The maternal morphogen bicoid (bcd) initiates the anterior gt pattern, while nanos (nos) plays a role in the posterior pattern. Gene dosage studies indicate that different thresholds of the bcd gradient might trigger hb and gt expression, resulting in overlapping but noncoincident patterns of expression. We also present evidence that different concentrations of hb protein are instructive in defining the limits of kni and gt expression within the presumptive abdomen. These results suggest that gt is a bona fide gap gene, which acts with hb, Kruppel and kni to initiate striped patterns of gene expression in the early embryo.
TL;DR: The Dictyostelium ecmB gene encodes an extracellular matrix protein and is inducible by the stalk cell morphogen DIF and is expressed in a subset of prestalk cells in the slug and surrounding pstA cells first express it at culmination.
TL;DR: In situ and dot-blot hybridization analyses have revealed that GHox-8 is expressed in limb bud mesoderm in a temporal and spatial fashion consistent with its involvement in specifying anterior positional identity, which is a member of a family of vertebrate homeobox-containing genes that are highly similar in sequence to the Drosophila msh gene.
TL;DR: It is shown that RA, a naturally occurring morphogen implicated in embryonic development, can selectively regulate the expression of integrin complexes in neuronal cells and suggest an important role of the alpha 1/beta 1 laminin receptor in the morphological differentiation of nerve cells.
Abstract: Retinoic acid (RA) is known to induce differentiation of neuroblastoma cells in vitro. Here we show that treatment of two human neuroblastoma cell lines, SY5Y and IMR32, with RA resulted in a fivefold increase of the integrin alpha 1/beta 1 expression. The effect was selective because expression of the alpha 3/beta 1 integrin, also present in these cells, was not increased. The up-regulation of the alpha 1/beta 1 differentiated SY5Y cells correlated with increased neurite response to laminin. In fact, RA-treated SY5Y cells elongated neurites on laminin-coated substratum more efficiently compared with untreated cells or cells treated with nerve growth factor, insulin, or phorbol 12-myristate 13-acetate. These three agents induced partial morphological differentiation but did not increase alpha 1 integrin expression. Neurite extension in RA-treated cells was more efficient on laminin than on fibronectin or collagen type I and was inhibited with beta 1 integrin antibodies on all three substrates. Affinity chromatography experiments showed that alpha 1/beta 1 is the major laminin receptor in both untreated and RA-treated SY5Y cells. These data show that RA, a naturally occurring morphogen implicated in embryonic development, can selectively regulate the expression of integrin complexes in neuronal cells and suggest an important role of the alpha 1/beta 1 laminin receptor in the morphological differentiation of nerve cells.
TL;DR: Results of recombination experiments and studies of changes in the apical ridge and proliferation in the mesenchYme suggest the following scheme: retinoic acid is involved in specification of position of mesenchyme cells; this specification determines their local interaction with the ridge that controls ridge morphology.
Abstract: The chick limb bud is a powerful experimental system in which to study pattern formation in vertebrate embryos. Exogenously applied retinoic acid, a vitamin A derivative, can bring about changes in pattern and, on several grounds, is a good candidate for an endogenous morphogen. As such, the local concentration of retinoic acid might provide cells with information about their position in relation to one axis of the limb. Alternatively, retinoic acid may be part of a more complex signalling system. Homeobox genes are possible target genes for regulation by retinoic acid in the limb. In particular, one homeobox gene, XlHbox 1 is expressed locally in the mesenchyme of vertebrate forelimbs and might code for an anterior position. When the pattern of the chick wing is changed by retinoic acid or by grafts of signalling tissue such that anterior cells now form posterior structures, the domain of XlHbox 1 expression expands rather than contracts. The expansion of XlHbox 1 expression correlates with shoulder girdle abnormalities. Retinoic acid application leads to visible changes in bud shape and this allows dissection of the way in which patterning is co-ordinated with morphogenesis. Results of recombination experiments and studies of changes in the apical ridge and proliferation in the mesenchyme suggest the following scheme: retinoic acid is involved in specification of position of mesenchyme cells; this specification determines their local interaction with the ridge that controls ridge morphology; the thickened apical ridge permits local proliferation in the underlying mesenchyme.(ABSTRACT TRUNCATED AT 250 WORDS)
TL;DR: Dictyostelium uses soluble factors to regulate morphogenesis and cellular differentiation through signal transduction pathways mediated by cyclic AMP through cell surface receptors coupled to G proteins, and that others are mediated by the morphogen DIF.
TL;DR: This chapter describes the zygotically active genes that specify the dorsal, the ventral pattern of the Drosophila embryo, and how these genes respond to a gradient of maternal positional information that defines their realms of activity.
Abstract: Publisher Summary This chapter describes the zygotically active genes that specify the dorsal, the ventral pattern of the Drosophila embryo These genes respond to a gradient of maternal positional information that defines their realms of activity, and they, in turn, fix these domains and may direct subsequent patterning within these regions Since these genes respond to and interpret maternal positional information, they are, in a sense, the dorsal–ventral counterparts of the anterior–posterior segmentation genes Most of the zygotically expressed genes, known to be required for the dorsal–ventral patterning in the embryo, are defined in the saturation mutagenesis experiments From the cuticular phenotypes of the differentiated mutant embryos, genes that are required to allow the normal development of specific regions of the dorsal–ventral pattern are identified The analysis of the mutant phenotypes and the molecular characterization of the regulation and activity of the zygotically required dorsal–ventral patterning genes have provided important insights into the relationships between the cell position and differentiated fate Three primary dorsal–ventral embryonic fields are defined in response to the maternal morphogen gradient To establish these three fields, zygotically active dorsal–ventral patterning genes are transcribed locally in response to define the thresholds of maternal morphogen, and, in addition, the activities of their gene products are also essential in defining the extents of the three fields
TL;DR: It is reported that the heterologous junctions between the normal and transformed cells respond in the opposite direction; their permeability is reduced by retinoic acid (greater than or equal to 10(-9) M) and its benzoic acid derivative tetrahydrotetramethylnaphthalenylpropenylbenzoic acids.
Abstract: The permeability of junctions between cells of the same type (homologous junctions) is greatly increased by retinoic acid (10(-9)-10(-8) M), a probable morphogen, and this responsiveness is shared by a variety of normal and transformed cell types (Mehta, P.P., J.S. Bertram, and W.R. Loewenstein. 1989. J. Cell Biol. 108:1053-1065). Here we report that the heterologous junctions between the normal and transformed cells respond in the opposite direction; their permeability is reduced by retinoic acid (greater than or equal to 10(-9) M) and its benzoic acid derivative tetrahydrotetramethylnaphthalenylpropenylbenzoic acid (greater than or equal to 10(-11) M). The opposite responses of the two classes of junction are shown to be concurrent; in cocultures of normal 10T1/2 cells and their methylcholanthrene-transformed counterparts, the permeability of the heterologous junctions, which is lower than that of the homologous junctions to start with, falls (within 20 h of retinoid application), at the same time that the permeability of the homologous junctions rises in both cell types. Such a counter-regulation requires a minimum of three degrees of cellular differentiation. A model is proposed in which the differentiations reside in a trio of junctional channel protein. The principle of the model may have wide applications in the regulation of intercellular communication at tissue boundaries, including embryonic ones.
Journal Article•
TL;DR: It is possible that RA is important for the normal pattern formation in these regions and acts as a morphogen as previously proposed in limb development.
Abstract: Cephalic neural crest cells are known to form the frontonasal mesenchyme and contribute to the mesenchyme of the visceral arches. Retinoids affect neural crest cells and their derivatives during development, and thus cause craniofacial, thymus, and conotruncal heart malformations. In addition, retinoids induce malformations of the central nervous system (CNS). Retinoic acid (RA) and its congeners accumulate in a saturable manner in neural crest and neural crest-derived cells, in the hindbrain, and the spinal cord of mouse embryos. Cellular retinoic acid-binding protein (CRABP) was localized by immunohistochemistry in the same areas as were the labelled RA congeners. Thus, CRABP and RA congeners were found in the transitional zone between surface ectoderm and neuropeithelium, from where neural crest cells are known to emanate (day 8 1/2). Later, specific labelling was found in the frontonasal mesenchyme and in the visceral arches. Also in the trunk, neural crest cells were labelled. In CNS, strong staining was seen in the rhombomeres (especially numbers 4-6) of the hindbrain and in the spinal cord. Retinol and cellular retinol-binding protein (CRBP) were more evenly distributed, with exception of surface ectoderm, epithelium of gut, and myocardium, where CRBP was specifically expressed. These findings are discussed in relation to the differential expression of nuclear RA receptors and homeobox genes in the craniofacial region and in the hindbrain. It is possible that RA is important for the normal pattern formation in these regions and acts as a morphogen as previously proposed in limb development.
TL;DR: This is the first human endogenous retroviral mRNA that is known to be transcriptionally activated by RA and is named RRHERV-I, which shows a strong homology to the type C-related human endogenous Retroviral proviruses ERV3 and 4-1.
Abstract: Retinoic acid (RA), a developmental morphogen, causes activation of a transcript of an endogenous retrovirus-related element in the human teratocarcinoma-derived cell line PA-1. This provirus is defective, and the provirus-related sequences exist as multicopy elements (more than 20 copies) in human DNA. This is the first human endogenous retroviral mRNA that is known to be transcriptionally activated by RA. The nucleotide sequence of the 3,357 bp of this viral cDNA was determined and shows a strong homology to the type C-related human endogenous retroviral proviruses ERV3 and 4-1. This cDNA contains 'R-U5-delta pol-env-U3-R sequences of the provirus. Adjacent to the putative 5' long terminal repeat of this provirus there is an 18-bp sequence complementary to the 3' end of isoleucine tRNA. We named this RA-responsive virus RRHERV-I.
01 Jul 1991
TL;DR: The characterization of head activator (HA) as a morphogen capable of increasing the number of tentacles regenerated by hydra was re-examined and axial-specific effects of HA on the initiation and extent of head-specific epithelial cell differentiation were examined.
Abstract: The characterization of head activator (HA) as a morphogen capable of increasing the number of tentacles regenerated by hydra was re-examined. Gastric tissue was excised from HA-treated whole animals and allowed to regenerate. At the cellular level the differentiation of head-specific ectodermal epithelial cells was monitored by quantifying monoclonal antibody, CP8, labeling. This labeling has been correlated with a rise in head activation potential and the determination of tissue to form head structures (Javois et al. 1986). At the morphological level tentacle number was monitored. HA-treated regenerates began the head patterning processes and evaginated tentacles sooner than controls but did not produce extra tentacles. The kinetics of CP8 labeling did not reveal major differences between treated and control regenerates after the initiation of head-specific epithelial cell differentiation. HA appeared to act more like a growth factor stimulating the differentiation of head-specific cell types rather than a morphogen which altered head morphology. An additional aspect of the study examined axial-specific effects of HA on the initiation and extent of head-specific epithelial cell differentiation. The cellular response of ectodermal epithelial cells to HA was dependent on their original axial location. More CP8+ tissue differentiated in regenerates of apical as opposed to mid-gastric origin.
TL;DR: Although the genes involved in transducing signals provided by morphogens are still unknown, homeobox genes, which specify positional information in Drosophila and possibly in vertebrate embryogenesis, are among the suggested candidates.
Abstract: Morphogens, i.e., endogenous, diffusible molecules which induce pathways of differentiation through a gradient of concentration, play a key role in vertebrate development. Retinoic acid (RA) is a natural morphogen in chicken development, where it specifies the limb anteroposterior (AP) axis (Tickle et al. 1982; Thaller and Eichele 1987, 1988; Brockes 1989), and possibly in frogs, where alteration of intraembryonic RA levels dramatically affects the AP polarity of the developing CNS (Durston et al., 1989). The identification of three nuclear RA receptors in mouse and man (Petkovich et al. 1987; Giguere et al. 1987; Brand et al. 1988; Zelent et al. 1989) supports the concept that the morphogens act as intracellular signal molecules with direct gene control functions. Although the genes involved in transducing signals provided by morphogens are still unknown, homeobox genes, which specify positional information in Drosophila and possibly in vertebrate embryogenesis (Gehring 1987; Ingham 1988; Holland and Hogan 1988), are among the suggested candidates (Brockes 1989; de Robertis et al. 1989).
01 Jan 1991
TL;DR: In order to undestand better the molecular mechanism for RA action, it is important to characterize the multiple components involved in the interpretation of the signal provided by RA and/or its plausible concentration gradients.
Abstract: The pleiotropic effects that RA exerts during vertebrate development have been studied in a number of experimental systems. For example, retinoic acid (RA) is thought to be the morphogen released by the zone of polarizing activity (ZPA) in the developing chick limb bud (see Smith et al., 1989) for review, and also several other articles in the present book). RA has also been implicated in the patterning of the antero/posterior axis of the body in Xenopus (Durston et al., 1989; Sive et al., 1990), and of the developing CNS in chicken (Wagner et al., 1990). It appears therefore that RA might have been selected as a molecule which plays a crucial role in directing pattern formation in vertebrate development. In order to undestand better the molecular mechanism for RA action, it is important to characterize the multiple components involved in the interpretation of the signal provided by RA and/or its plausible concentration gradients.
01 Jan 1991
TL;DR: In this paper, the authors used the vertebrate limb development as a model system to discuss some circumstantial evidence that RA, RARs and Hox genes may also be functionally related in vivo, in light of recent findings concerning the expression of such genes during mouse development.
Abstract: The murine genome contains at least 30 sequences related to the Drosophila Antennapedia homeobox. The so-called Hox genes are clustered in four complexes conserved throughout vertebrate evolution1–5, and accumulating evidence shows that these genes are expressed during ontogenesis in a coordinated manner3,6–8 and may be involved in a regulatory network controlling vertebrate morphogenesis. Retinoic acid (RA) or related retinoid derivatives are candidates for crucial signalling molecules involved in vertebrate morphogenetic processes and/or pattern formation as best exemplified by the developing and regenerating limb system (reviewed in refs. 9,10). RA can interfere very specifically with anteroposterior (A-P) patterning in the chick wing bud 11 and is believed to be a natural morphogen released as a concentration gradient from a discrete posterior area, the zone of polarizing activity (ZPA)12. RA can also disturb positional information in the regenerating amphibian limb13,14 The molecular basis of RA activity involves its binding to a cellular RA binding protein (CRABP) 15 and/or to an appropriate nuclear RA receptors (RARs). An increasing number of such RA receptors are being characterized and all of them are ligand-inducible transcription factors belonging to the steroid hormones receptors family16–19. There is increasing evidence that in cultured cells, RA regulates the steady state level of Hox genes messenger RNAs though the transcriptional or post-transcriptional nature of this regulation is not yet clearly established (see e.g. ref.20). In addition, the human Hox-2 genes respond to RA treatment, in teratocarcinoma cell lines, in a way related to their respective positions within the Hox-2 complex21. The molecular mechanism involved in such a colinear response is not known but probably parallels those regulating the expression of these genes during ontogenesis. Using the vertebrate limb development as a model system, we would like to discuss here some circumstantial evidence that RA, RARs and Hox genes may also be functionally related in vivo, in the light of recent findings concerning the expression of such genes during mouse development.