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PubMed1996

Drosophila TFIIA-S is up-regulated and required during Ras-mediated photoreceptor determination.

Photoreceptor induction in the developing Drosophila eye is triggered by the activation of the Ras pathway. Subsequently, the Ras-mediated activation of site-specific transcription factors leads to the expression of putative "effector" genes. The coactivator function of the basal transcription factor TFIIA has been shown previously to enhance the trans-activation potential of site-specific transcription factors in vitro. Here, we show that the expression of the small subunit of TFIIA (dTFIIA-S) is specifically up-regulated in a transient manner during Ras-mediated photoreceptor induction. Furthermore, although null mutations in dTFIIA-S are cell lethal, a hypomorphic dTFIIA-S allele demonstrates an increased requirement for this factor during photoreceptor development. In addition, the cone cell to R7 photoreceptor transformation caused by ectopic activation of the Ras pathway during eye development is suppressed by the removal of one functional copy of the dTFIIA-S locus revealing the sensitivity of this process to reductions in dTFIIA-S activity. These results are the first in vivo evidence for the coactivator function in transcriptional enhancement proposed for TFIIA.

Animals↗
PubMed1999

DIO-1 is a gene involved in onset of apoptosis in vitro, whose misexpression disrupts limb development.

The DIO-1 (death inducer-obliterator-1) gene, identified by differential display PCR in pre-B WOL-1 cells undergoing apoptosis, encodes a putative transcription factor whose protein has two Zn finger motifs, nuclear localization signals, and transcriptional activation domains, expressed in the limb interdigitating webs during development. When overexpressed, DIO-1 translocates to the nucleus and activates apoptosis in vitro. Nuclear translocation as well as induction of apoptosis are lost after deletion of the nuclear localization sequences. DIO-1 apoptotic induction is prevented by caspase inhibitors and Bcl-2 overexpression. The in vivo role of DIO-1 was studied by misexpressing DIO-1 during chicken limb development. The most frequently observed phenotype was an arrest in limb outgrowth, an effect that correlates with the inhibition of mesodermal and ectodermal genes involved in this process. Our data demonstrate the ability of DIO-1 to trigger apoptotic processes in vitro and suggest a role for this gene in cell death during development.

Amino Acid Sequence↗
PubMed1997

A binding site for Gli proteins is essential for HNF-3beta floor plate enhancer activity in transgenics and can respond to Shh in vitro.

The floor plate plays important roles in ventral pattern formation and axonal guidance within the neural tube of vertebrate embryos. A critical event for floor plate development is the induction of a winged helix transcription factor, Hepatocyte Nuclear Factor-3beta (HNF-3beta). The enhancer for floor plate expression of HNF-3beta is located 3' of the transcription unit and consists of multiple elements. HNF-3beta induction depends on the notochord-derived signal, Sonic hedgehog (Shh). Genetic analysis in Drosophila has led to the identification of genes involved in the Hh signalling pathway, and cubitus interruptus (ci), encoding a protein with five zinc finger motifs, was placed downstream. In the present work, we test the involvement of Gli proteins, the mouse homologues of Ci, in activation of the floor plate enhancer of HNF-3beta. Transgenic analysis shows that a Gli-binding site is required for the activity of the minimal floor plate enhancer of HNF-3beta in vivo. Three Gli genes are differentially expressed in the developing neural tube. Gli expression is restricted to the ventral part, while Gli2 and Gli3 are expressed throughout the neural tube and dorsally, respectively. Strong Gli and Gli2, and weak Gli3 expressions transiently overlap with HNF-3beta at the time of its induction. Consistent with ventrally localized expression, Gli expression can be up-regulated by Shh in a cell line. Finally, the Gli-binding site acts as a Shh responsive element, and human GLI, but not GLI3, can activate this binding site in tissue culture. Taken together, these findings suggest that Gli, and probably also Gli2, are good candidates for transcriptional activators of the HNF-3beta floor plate enhancer, and the binding site for Gli proteins is a key element for response to Shh signalling. These results also support the idea that Gli/Ci are evolutionary conserved transcription factors in the Hedgehog signalling pathway.

Animals↗
PubMed2001

Initial patterning of the central nervous system: how many organizers?

For three-quarters of a century, developmental biologists have been asking how the nervous system is specified as distinct from the rest of the ectoderm during early development, and how it becomes subdivided initially into distinct regions such as forebrain, midbrain, hindbrain and spinal cord. The two events of 'neural induction' and 'early neural patterning' seem to be intertwined, and many models have been put forward to explain how these processes work at a molecular level. Here I consider early neural patterning and discuss the evidence for and against the two most popular models proposed for its explanation: the idea that multiple signalling centres (organizers) are responsible for inducing different regions of the nervous system, and a model first articulated by Nieuwkoop that invokes two steps (activation/transformation) necessary for neural patterning. As recent evidence from several systems challenges both models, I propose a modification of Nieuwkoop's model that most easily accommodates both classical and more recent data, and end by outlining some possible directions for future research.

Animals↗
PubMed2000

Activation of fgf4 gene expression in the myotomes is regulated by myogenic bHLH factors and by sonic hedgehog.

The Fgf4 gene encodes an important signaling molecule which is expressed in specific developmental stages, including the inner cell mass of the blastocyst, the myotomes, and the limb bud apical ectodermal ridge (AER). Using a transgenic approach, we previously identified overlapping but distinct enhancer elements in the Fgf4 3' untranslated region necessary and sufficient for myotome and AER expression. Here we have investigated the hypothesis that Fgf4 is a target of myogenic bHLH factors. We show by mutational analysis that a conserved E box located in the Fgf4 myotome enhancer is required for Fgf4-lacZ expression in the myotomes. A DNA probe containing the E box binds MYF5, MYOD, and bHLH-like activities from nuclear extracts of differentiating C2-7 myoblast cells, and both MYF5 and MYOD can activate gene expression of reporter plasmids containing the E-box element. Analyses of Myf5 and MyoD knockout mice harboring Fgf4-lacZ transgenes show that Myf5 is required for Fgf4 expression in the myotomes, while MyoD is not, but MyoD can sustain Fgf4 expression in the ventral myotomes in the absence of Myf5. Sonic hedgehog (Shh) signaling has been shown to have an essential inductive function in the expression of Myf5 and MyoD in the epaxial myotomes, but not in the hypaxial myotomes. We show here that expression of an Fgf4-lacZ transgene in Shh-/- embryos is suppressed not only in the epaxial but also in the hypaxial myotomes, while it is maintained in the AER. This suggests that Shh mediates Fgf4 activation in the myotomes through mechanisms independent of its role in the activation of myogenic factors. Thus, a cascade of events, involving Shh and bHLH factors, is responsible for activating Fgf4 expression in the myotomes in a spatial- and temporal-specific manner.

3' Untranslated Regions↗
PubMed2005

Sonic hedgehog and retinoic acid are not sufficient to induce motoneuron generation in the avian caudal neural tube.

The caudal neural tube (CNT) of the avian embryo is devoid of both dorsal and ventral roots. We show that the lack of ventral roots in the CNT, from somite 48 caudalwards, is due to an absence of post-mitotic motoneurons (MNs). The absence of MNs is not due to a defective notochordal induction since Sonic Hedgehog (SHH) signaling is intact and the caudal notochord is able to induce ectopic MNs when grafted laterally to a host neural tube. The transcription factors involved in MN specification (Pax6, Nkx6.1, and Olig2) are all expressed in the CNT, despite the lower expression level of Pax6, but an overlap between Olig2 and the ventrally expressed transcription factor Nkx2.2 is observed in the CNT. Grafting a quail CNT into the cervical level of a chick host rescues MN generation, demonstrating both the CNT potential for MN generation and the key role of the caudal environment in the MN differentiation blockade. The transplantation of the CNT-flanking somites into the cervical level does not inhibit MN generation. Furthermore, implantation of a retinoic-acid-soaked bead laterally to the CNT does not rescue MN generation. Together, these data indicate that the rostral environment contains a signal different from both SHH and Retinoic Acid that acts on MN differentiation.

Animals↗
PubMed2000

Visceral endoderm mediates forebrain development by suppressing posteriorizing signals.

The anterior visceral endoderm (AVE) has attracted recent attention as a critical player in mouse forebrain development and has been proposed to act as "head organizer" in mammals. However, the precise role of the AVE in induction and patterning of the anterior neuroectoderm is not yet known. Here we identified a 5'-flanking region of the mouse Otx2 gene (VEcis) that governs the transgene expression in the visceral endoderm. In transgenic embryos, VEcis-active cells were found in the distal visceral endoderm at 5.5 days postcoitus (dpc), had begun to move anteriorly at 5.75 dpc, and then became restricted to the AVE prior to gastrulation. The VEcis-active visceral endoderm cells exhibited ectodermal morphology distinct from that of the other endoderm cells and consisted of two cell layers at 5.75 dpc. In the Otx2(-/-) background, the VEcis-active endoderm cells remained distal even at 6.5 dpc when a primitive streak was formed; anterior definitive endoderm was not formed nor were any markers of anterior neuroectoderm ever induced. The Otx2 cDNA transgene under the control of the VEcis restored these Otx2(-/-) defects, demonstrating that Otx2 is essential to the anterior movement of distal visceral endoderm cells. In germ-layer explant assays between ectoderm and visceral endoderm, the AVE did not induce anterior neuroectoderm markers, but instead suppressed posterior markers in the ectoderm; Otx2(-/-) visceral endoderm lacked this activity. Thus Otx2 is also essential for the AVE to repress the posterior character. These results suggest that distal visceral endoderm cells move to the future anterior side to generate a prospective forebrain territory indirectly, by preventing posteriorizing signals.

Animals↗
PubMed1989

Positional information revisited.

Positional information has been suggested to play a central role in pattern formation during development. The strong version of positional information states that there is a cell parameter, positional value, which is related to position as in a coordinate system and which determines cell differentiation. A weaker version merely emphasises position as a key determinant in cell development and differentiation. There is evidence for boundaries and orthogonal axes playing an important role in positional systems. A positional signal is distinguished from an inductive interaction because the former specifies multiple states, confers polarity, and can act over a long range. A gradient in a diffusible morphogen is just one way of specifying position. There is now good evidence in several systems for substances which may be the morphogen for positional signalling. The product of the bicoid gene in early Drosophila development is the best prospect. Retinoic acid is unique in its ability to alter positional value and may also be a morphogen. The best evidence for positional value, a concept fundamental to positional information, remains a biological assay based on grafting. The idea of positional value uncouples differentiation and position, and allows considerable freedom for patterning. It is not clear whether positional value or differentiation involves a combinatorial mechanism. Interpretation of positional information remains a central problem. There is good evidence that cells can respond differentially to less than a two-fold change in concentration of a chemical signal. It may be that interpretation involves listing the sites at which a particular class of cell differentiation will occur. The problem is made less severe when blocks of cells are specified together as in mechanisms based on an isomorphic prepattern. Isomorphic prepatterns could establish repeated structures which are equivalent and which are then made non-equivalent by positional information. This would enable local differences to develop. The combination of these two mechanisms may be wide-spread. There is evidence that positional signals within a single animal and in related animals are conserved. It is not clear just how wide this conservation is, but it is at phylotypic stages, rather than in eggs, that similarity might be expected. It is nevertheless impressive that the polar coordinate model can be applied to regulation in systems as diverse as insects, vertebrates and protozoa. The molecular basis of positional signalling is just becoming accessible; the molecular basis of positional value is still awaited. A brief personal history of positional information is provided in an appendix.

Animals↗
PubMed1993

Suppression of tumorigenicity in temperature-sensitive mutants of embryonal carcinoma cells by induction of cell differentiation at non-permissive temperature.

The temperature-sensitive (ts) mutants of cell differentiation derived from the mouse teratocarcinoma cell line F9, when exposed to non-permissive temperature, undergo stem-cell differentiation concomitant with a transient retardation of cell-cycle progression. By incubating these mutant strains at non-permissive temperature, we were able to study the relationship between cell differentiation and tumorigenicity. Upon exposure to non-permissive temperature, the mutant cells undergo extensive differentiation and lose their ability to initiate tumors in vivo, but retain their in vitro proliferative potential. Our data suggest that the loss of tumorigenicity is not caused by altered proliferative potential, but rather by cell differentiation. We therefore suggest that the loss of proliferative potential and the onset of cell differentiation in teratocarcinoma F9 cells are 2 independent events which can be genetically dissected, and that there is (a) crucial step(s) in the differentiation pathway at which these ts mutant cells lose their tumorigenicity.

Alkaline Phosphatase↗
PubMed2000

Presenilin 2 expression in neuronal cells: induction during differentiation of embryonic carcinoma cells.

Mutations in the presenilin 1 and 2 (PS1 and PS2) genes cause most cases of early onset Alzheimer's disease. The genes encode two homologous multipass membrane proteins. Since the endogenous expression of PS2 has been poorly analyzed to date, we studied PS2 expression and localization in cultured human neuroblastoma cells and mouse neuronal cells. PS2 was mainly detected as a full-length protein of about 52 kDa in these cells and in brain, in contrast to PS1 that is mainly detected as endoproteolytic N-terminal and C-terminal fragments. Using immunofluorescence we found that like PS1, PS2 colocalized with markers of the endoplasmic reticulum-Golgi intermediate compartment, ERGIC-53 and beta-COP. Double labeling for PS1 and PS2 indicated that both proteins are colocalized in neuroblastoma SH-SY5Y cells. To study PS2 expression during differentiation, mouse embryonic carcinoma P19 cells were treated with retinoic acid. We found minimal PS2 expression in undifferentiated cells, an increase from day 2, and a maximum at day 8 after treatment. PS1 expression remained constant during this period. The differential expression of PS1 and PS2 within the P19 cells following retinoic acid treatment indicates different utilization or temporal requirements for these proteins during neuronal differentiation.

Alzheimer Disease↗
PubMed1989

Effects of induction of anti-embryonation immunity on liver granulomas, spleen weight and portal pressure in mice infected with Schistosoma japonicum.

BALB/c mice sensitized with injections of viable immature Schistosoma japonicum eggs had significantly fewer and smaller granulomas in the liver, lower portal pressure and smaller spleens at D + 75 of infection compared to similarly infected unsensitized controls. The portal pressure and spleen weights of the mice sensitized with immature eggs were not different from uninfected unsensitized mice of similar ages at D + 75 of infection. The results strongly support our hypothesis that it should be possible to prevent serious hepatosplenic disease in schistosomiasis japonica by vaccination to induce anti-embryonation immunity.

Animals↗
PubMed1983

Induction of differentiation of embryonal carcinoma cells by retinol: possible mechanisms.

Retinol, like retinoic acid, can induce differentiation of two embryonal carcinoma cell lines. These cells contain the specific retinol binding proteins in the cytosolic fractions. No correlation was found between the levels of binding activity and the effectiveness of retinol to induce differentiation. Microsomal fractions of embryonal carcinoma cells catalyse mannosyl transfer from GDP-mannose to retinyl phosphate. The formation of mannosyl retinyl phosphate appears a constitutive property and can be a mechanism by which retinoids induce early cell surface changes during differentiation of embryonal carcinoma cells.

Animals↗
PubMed1982

Preferential induction of fetal versus embryonic globin chains in human leukemic cell lines.

By use of a newly developed technique combining affinity chromatography of hemoglobin on haptoglobin-Sepharose and IEF of globin chains, we analyzed the globin synthetic pattern of human K562 cells in both the basal state and after addition of several potential inducers. Hemin only was found effective: its addition at 50 microM results in a quantitative increase of globin chain synthesis (from 0.3 to 1% up to 5%) and a qualitative "switch" with a striking increase of alpha and a decrease of epsilon and zeta chains (relative to the prevailing gamma chains). This system, in which hemin induces changes that mimic to some extent the normal embryonic-fetal switch, might therefore provide a cellular model for investigating molecular mechanisms of globin gene regulation. In addition similar results were obtained with a different human myeloid leukemia cell line, the KG1, thus raising the possibility that the expression of embryonic globin genes in malignant cells might not be simply the consequence of abnormal gene expression but rather reflect a possibly physiological differentiation phenomenon.

Animals↗
PubMed2006

Induction of melanocytes from embryonic stem cells and their therapeutic potential.

Embryonic stem (ES) cells from many organisms have the capacity to generate in vitro a wide variety of cell types depending on their environment. Understanding precisely how such toti- or pluripotent cells may be driven towards a specific lineage represents a major challenge if our ambition of using ES cells to generate a ready supply of healthy cells for cell-based therapies for a range of diseases is to be realized. Recent advances have demonstrated that melanocytes and retinal pigmented epithelial (RPE) cells exhibiting the characteristics of their natural counterparts can be induced from undifferentiated ES cells grown on monolayers of specific stromal cell lines or by using a combination of Wnt3a, Endothelin-3 and SCF. The ability to induce pigment cells from ES cells promises to facilitate our understanding of the precise molecular mechanisms underlying this process and moreover enable us to distinguish the program of gene expression that underpins the choice made between generating a nerual crest-type melanocyte versus an RPE cell. Moreover, once the combination of signals required to induce a particular type of pigment cell are characterized, the way may be open for future cell-based therapy for various diseases caused by defective pigment cells.

Animals↗