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PubMed1988

The polyomavirus enhancer comprises multiple functional elements.

The polyomavirus enhancer occupies 244 base pairs within noncoding sequences between the early and late transcription units. To define more precisely the DNA sequences that make up the enhancer, we cloned it together with the viral early promoter upstream of a reporter gene, isolated mutants bearing deletions introduced in vitro in the enhancer, and measured the capacity of the various mutant genomes to express the cat gene after transient transfection into mouse 3T3 cells. Analysis of a large number of deletion mutants revealed that the enhancer is between 102 and 172 base pairs long and can be divided into at least three functional elements. Relative to the entire enhancer, individual elements possessed little or no enhancer activity. However, pairs of elements enhanced transcription to levels much higher than the sum of individual elements approximating the activity of the complete enhancer. These findings support the view that the polyomavirus enhancer is composed of multiple sequence elements that function combinatorily and imply that a measure of cooperation exists in the interaction between cellular protein factors bound to their cognate sites in the enhancer and the transcriptional machinery of the cell.

Animals↗

PubMed1991

Functional similarities between human immunodeficiency virus type 1 and simian virus 40 kappa B proto-enhancers.

To search for broadly active enhancer elements within the human immunodeficiency virus type 1 (HIV-1) long terminal repeat, we have used a proto-enhancer amplification assay. In this assay, the enhancer region of simian virus 40 (SV40) is replaced by heterologous regulatory sequences. Upon passage in African green monkey kidney cells. SV40 growth revertants can arise by amplification (usually duplication) of active protoenhancers within the heterologous sequences. Most of the HIV-1 U3 regulatory sequences were assayed; only amplification of one or both of the HIV-1 enhancer core kappa B motifs consistently resulted in viable SV40 virus. Examination of the cell-specific enhancer activity of the individual HIV-1 kappa B proto-enhancers showed that, like the broadly active SV40 kappa B proto-enhancer (C proto-enhancer), they are all active in noninduced cell lines of either lymphoid (H9 and Jurkat) or nonlymphoid (HeLa and CV-1) origin. Unexpectedly, one of three kappa B point mutants that exhibit little or no activity in unstimulated cells is as highly induced in stimulated Jurkat cells as are the wild-type kappa B proto-enhancers. This point mutation shows that kappa B-related proto-enhancers can display markedly different activation properties in unstimulated cells yet still activate transcription to similar levels in stimulated cells.

Animals↗

PubMed1999

Tandemization of a subregion of the enhancer sequences from SRS 19-6 murine leukemia virus associated with T-lymphoid but not other leukemias.

Most simple retroviruses induce tumors of a single cell type when infected into susceptible hosts. The SRS 19-6 murine leukemia virus (MuLV), which originated in mainland China, induces leukemias of multiple cellular origins. Indeed, infected mice often harbor more than one tumor type. Since the enhancers of many MuLVs are major determinants of tumor specificity, we tested the role of the SRS 19-6 MuLV enhancers in its broad disease specificity. The enhancer elements of the Moloney MuLV (M-MuLV) were replaced by the 170-bp enhancers of SRS 19-6 MuLV, yielding the recombinants DeltaMo+SRS(+) and DeltaMo+SRS(-) M-MuLV. M-MuLV normally induces T-lymphoid tumors in all infected mice. Surprisingly, when neonatal mice were inoculated with DeltaMo+SRS(+) or DeltaMo+SRS(-) M-MuLV, all tumors were of T-lymphoid origin, typical of M-MuLV rather than SRS 19-6 MuLV. Thus, the SRS 19-6 MuLV enhancers did not confer the broad disease specificity of SRS 19-6 MuLV to M-MuLV. However, all tumors contained DeltaMo+SRS M-MuLV proviruses with common enhancer alterations. These alterations consisted of tandem multimerization of a subregion of the SRS 19-6 enhancers, encompassing the conserved LVb and core sites and adjacent sequences. Moreover, when tumors induced by the parental SRS 19-6 MuLV were analyzed, most of the T-lymphoid tumors had similar enhancer alterations in the same region whereas tumors of other lineages retained the parental SRS 19-6 MuLV enhancers. These results emphasize the importance of a subregion of the SRS 19-6 MuLV enhancer in induction of T-cell lymphoma. The relevant sequences were consistent with crucial sequences for T-cell lymphomagenesis identified for other MuLVs such as M-MuLV and SL3-3 MuLV. These results also suggest that other regions of the SRS 19-6 MuLV genome contribute to its broad leukemogenic spectrum.

3T3 Cells↗

PubMed2001

Type B leukemogenic virus has a T-cell-specific enhancer that binds AML-1.

Type B leukemogenic virus (TBLV) induces rapidly appearing T-cell tumors in mice. TBLV is highly related to mouse mammary tumor virus (MMTV) except that TBLV long terminal repeats (LTRs) have a deletion of negative regulatory elements and a triplication of sequences flanking the deletion. To determine if the LTR triplication represents a viral enhancer element, we inserted the triplication upstream and downstream in either orientation relative to the thymidine kinase promoter linked to the luciferase gene. These experiments showed that upregulation of reporter gene activity by the TBLV triplication was relatively orientation independent, consistent with the activity of eukaryotic enhancer elements. TBLV enhancer activity was observed in T-cell lines but not in fibroblasts, B cells, or mammary cells, suggesting that enhancer function is cell type dependent. To analyze the transcription factor binding sites that are important for TBLV enhancer function, we prepared substitution mutations in a reconstituted C3H MMTV LTR that recapitulates the deletion observed in the TBLV LTR. Transient transfections showed that a single mutation (556M) decreased TBLV enhancer activity at least 20-fold in two different T-cell lines. This mutation greatly diminished AML-1 (recently renamed RUNX1) binding in gel shift assays with a mutant oligonucleotide, whereas AML-1 binding to a wild-type TBLV oligomer was specific, as judged by competition and supershift experiments. The 556 mutation also reduced TBLV enhancer binding of two other protein complexes, called NF-A and NF-B, that did not appear to be related to c-Myb or Ets. AML-1 overexpression in a mammary cell line enhanced expression from the TBLV LTR approximately 30-fold. These data suggest that binding of AML-1 to the TBLV enhancer, likely in combination with other factors, is necessary for optimal enhancer function.

Animals↗

PubMed1990

Functional organization of the hepatitis B virus enhancer.

We have studied the functional constituents of the hepatitis B virus enhancer in a number of cell lines. The sequence of this enhancer, being embedded within an open reading frame of the virus, is in part evolutionarily frozen and therefore serves as a good model to investigate the fundamental enhancer elements. The hepatitis B virus enhancer contains three functionally important DNA sequence elements, EP, E, and NF-1a, each of which is bound by a distinct protein(s). The synergistic action of these elements accounts for all of the enhancer activity in a nonliver cell line and for most, but not all, of the activity in liver-derived cell lines. Multimers of the E but not of the EP element act as an autonomous enhancer. Conversely, a single element of either the E or the NF-1a element can act only when linked to the EP element. These results suggest that EP is a crucial enhancer element that acts only in interaction with a second enhancer element with intrinsic enhancer activity. Interestingly, a highly similar enhancer structure is found in a number of distinct viruses.

Animals↗

PubMed1991

Functional characterization of the developmentally controlled immunoglobulin kappa 3' enhancer: regulation by Id, a repressor of helix-loop-helix transcription factors.

We have functionally characterized an enhancer element (kappa E3') which lies 8.5 kb downstream of the immunoglobulin kappa gene. The activity of this enhancer is developmentally controlled. It is inactive at the pre-B-cell stage but active at the B-cell and plasma cell stages. This enhancer is also functional in S107 plasmacytoma cells, which lack NF-kappa B and therefore intron enhancer activity. The activity of the kappa E3' enhancer therefore provides an explanation for the transcriptional activity of endogenous kappa genes in S107 cells in the absence of intron enhancer function. We have identified a 132-bp segment of the kappa E3' enhancer that retains 75% of the activity of the entire enhancer observed in plasmacytoma cells. Within this 132-bp core, there are at least two functional elements, one of which binds to a B-cell-specific nuclear factor. This element contains a potential binding site for the B-cell- and macrophage-specific transcription factor PU.1. The kappa intron and kappa E3' enhancers were also found to be regulatable by Id, an inhibitor of helix-loop-helix transcription factors. The site of action of Id on the kappa E3' enhancer was mapped to a 25-bp region which contains a potential binding site for a helix-loop-helix transcription factor. A possible model for the developmental control of kappa gene transcription is discussed.

Animals↗

PubMed1997

Synergistic activation of the fibroblast growth factor 4 enhancer by Sox2 and Oct-3 depends on protein-protein interactions facilitated by a specific spatial arrangement of factor binding sites.

Octamer binding and Sox factors are thought to play important roles in development by potentiating the transcriptional activation of specific gene subsets. The proteins within these factor families are related by the presence of highly conserved DNA binding domains, the octamer binding protein POU domain or the Sox factors HMG domain. We have previously shown that fibroblast growth factor 4 (FGF-4) gene expression in embryonal carcinoma cells requires a synergistic interaction between Oct-3 and Sox2 on the FGF-4 enhancer. Sox2 and Oct-3 bind to adjacent sites within this enhancer to form a ternary protein-DNA complex (Oct-3*) whose assembly correlates with enhancer activity. We now demonstrate that increasing the distance between the octamer and Sox binding sites by base pair insertion results in a loss of enhancer function. Significantly, those enhancer "spacing mutants" which failed to activate transcription were also compromised in their ability to form the Oct* complexes even though they could still bind both Sox2 and the octamer binding proteins, suggesting that a direct interaction between Sox2 and Oct-3 is necessary for enhancer function. Consistent with this hypothesis, Oct-3 and Sox2 can participate in a direct protein-protein interaction in vitro in the absence of DNA, and both this interaction and assembly of the ternary Oct* complexes require only the octamer protein POU and Sox2 HMG domains. Assembly of the ternary complex by these two protein domains occurs in a cooperative manner on FGF-4 enhancer DNA, and the loss of this cooperative interaction contributes to the defect in Oct-3* formation observed for the enhancer spacing mutants. These observations indicate that Oct-3* assembly results from protein-protein interactions between the domains of Sox2 and Oct-3 that mediate their binding to DNA, but it also requires a specific arrangement of the binding sites within the FGF-4 enhancer DNA. Thus, these results define one parameter that is fundamental to synergistic activation by Sox2 and Oct-3 and further emphasize the critical role of enhancer DNA sequences in the proper assembly of functional activation complexes.

Animals↗

PubMed1997

GABP factors bind to a distal interleukin 2 (IL-2) enhancer and contribute to c-Raf-mediated increase in IL-2 induction.

Triggering of the T-cell receptor-CD3 complex activates two major signal cascades in T lymphocytes, (i) Ca2+-dependent signal cascades and (ii) protein kinase cascades. Both signal cascades contribute to the induction of the interleukin 2 (IL-2) gene during T-cell activation. Prominent protein kinase cascades are those that activate mitogen-activated protein (MAP) kinases. We show here that c-Raf, which is at the helm of the classic MAP-Erk cascade, contributes to IL-2 induction through a distal enhancer element spanning the nucleotides from positions -502 to -413 in front of the transcriptional start site of the IL-2 gene. Induction of this distal IL-2 enhancer differs from induction of the proximal IL-2 promoter-enhancer, since it is induced by phorbol esters alone and independent from Ca2+ signals. In DNA-protein binding studies, we detected the binding of transcription factors GABP alpha and -beta to a dyad symmetry element (DSE) of the distal enhancer, which is formed by palindromic binding sites of Ets-like factors. Introduction of point mutations suppressing GABP binding to the DSE interfered with the induction of the distal enhancer and the entire IL-2 promoter-enhancer, while overexpression of both GABP factors enhanced the IL-2 promoter-enhancer induction. Overexpression of BXB, a constitutive active version of c-Raf, and of further members of the Ras-Raf-Erk signal cascade exerted an increase of GABP-mediated promoter-enhancer induction. In conjunction with previously published data on c-Raf-induced phosphorylation of GABP factors (E. Flory, A. Hoffmeyer, U. Smola, U. R. Rapp, and J. T. Bruder, J. Virol. 70:2260-2268, 1996), these results indicate a contribution of GABP factors to the Raf-mediated enhancement of IL-2 induction during T-cell activation.

Cloning, Molecular↗

PubMed1987

Metal-responsive elements act as positive modulators of human metallothionein-IIA enhancer activity.

The human metallothionein IIA (hMT-IIA) gene contains two enhancer elements whose activity is induced by heavy-metal ions such as Cd2+. To determine the nature of the relationship between the metal-responsive elements and the element(s) responsible for the basal activity of the enhancers, the basal-level enhancer element(s), the hMT-IIA enhancers were subjected to mutational analysis. We show that deletion of the metal-responsive elements had no effect on the basal activity of the enhancer but prevented further induction by Cd2+. On the other hand, replacement of the basal-level enhancer element with linker DNA led to inactivation of the enhancer both before and after treatment with Cd2+. Therefore, the metal-responsive elements seems to act as a positive modulator of enhancer function in the presence of heavy-metal ions. In addition to the two enhancers, the hMT-IIA promoter contained one other element, the GC box, required for its basal expression. Unlike deletion of the basal-level enhancer element, replacement of the GC box with linker DNA had no effect on the ability of the promoter to be induced by Cd2+.

Base Sequence↗

PubMed1988

Fine-structure mapping of the three mouse alpha-fetoprotein gene enhancers.

Multiple cellular enhancers have been identified previously in the 5'-flanking region of the mouse alpha-fetoprotein gene by transient expression assay. In this report the enhancers have been localized to three regions 200 to 300 base pairs in length at 2.5, 5.0, and 6.5 kilobases of DNA upstream of the transcriptional start site. Nucleotide sequence analysis of the three enhancers revealed areas of homology among them, the most significant of which were two regions of 10 and 18 nucleotides in length. Two of the enhancers were analyzed in detail and shown to be composed of multiple nonidentical domains, none of which was sufficient for full enhancer activity; rather, they acted in an additive fashion in generating the full activity of the enhancer. The tissue-specific activity of the enhancer at -2.5 kilobases was assessed by comparing the activities of subdomains in liver- and non-liver-derived cell lines and was found to be the result of both positive elements within the enhancer and at least one negative element to its 5' end. In contrast, the tissue specificity of the enhancer at -5.0 kilobases was maintained when the minimal essential region was tested alone. The nucleotide sequence similarities, as well as the differences among the enhancers, may explain their differing biological activities both in tissue culture and in vivo.

Animals↗

PubMed1988

Replication from a proximal simian virus 40 origin is severely inhibited by multiple reiterations of the 72-base-pair repeat enhancer sequence.

In a previous study in our laboratory, the effect of the reiteration frequency of the simian virus 40 (SV40) 72-base-pair (bp) repeat enhancer on transcription from the proximal SV40 early promoter was investigated (R. Kumar, T. A. Firak, C. T. Schroll, and K. N. Subramanian, Proc. Natl. Acad. Sci. USA 83:3199-3203, 1986). Increasing the enhancer copy number to four increased transcription proportionately; further increments in enhancer copy number reversed this effect, resulting in a decrease in the transcriptional activation. In the present study, the effect of enhancer reiteration on the replication efficiency of plasmids containing the SV40 origin of replication was investigated in transient replication assays in vivo in COS-1 monkey kidney cells producing the SV40 large tumor antigen required for replication. A plasmid containing the SV40 core origin and three copies of the replication-activating, G+C-rich 21-bp repeat promoter element replicated efficiently. Plasmids containing multiple copies of the 72-bp repeat enhancer cloned in head-to-tail linkage adjacent to the 21-bp repeat and the core origin replicated less efficiently; the decrease in replication efficiency could be correlated with the number of copies of the 72-bp repeat; replication was severely curtailed when 10 or more copies of the 72-bp repeat were present. Replication was not significantly inhibited by an increase in the number of copies of the 21-bp repeat to 15 or by the presence of three copies of a 360-bp pBR322 sequence in the immediate vicinity. Multiple copies of the 72-bp enhancer in cis were unable to inhibit replication from a second SV40 origin of replication situated 2 kilobase pairs away from the enhancer reiteration. Replication of four different test plasmids was not inhibited in trans by cotransfection of an excess of a potential competitor plasmid containing a 24-copy reiteration of the 72-bp enhancer. These results indicate that multiple tandem reiterations of the 72-bp enhancer inhibit replication only when they are present in cis adjacent to the origin of replication. Possible explanations for this inhibitory effect, such as an unfavorable local chromatin structure induced by the multimeric enhancer region or reduced or improper communications between factors bound to the multimeric region and the adjacent replication origin, are discussed.

Animals↗

PubMed2003

Colorectal neoplasms: role of intravenous contrast-enhanced CT colonography.

PURPOSE: To evaluate whether computed tomographic (CT) colonography with intravenously administered contrast material can help predict malignant differentiation of colorectal neoplasms (> or =10 mm in diameter). MATERIALS AND METHODS: Enhancement of 29 consecutive colorectal neoplasms on pre- and postcontrast CT colonographic images was retrospectively measured. The neoplasms were subsequently resected. Enhancement was calculated by subtraction of attenuation values (in Hounsfield units) obtained with precontrast and postcontrast 45-second-delay prone CT colonographic sequences. The neoplasms were graded as follows: grade 1, adenoma; grade 2, adenoma with high-grade dysplasia; grade 3, well-differentiated adenocarcinoma; grade 4, moderately differentiated adenocarcinoma; and grade 5, poorly differentiated adenocarcinoma. Correlation among size, histologic grade, and degree of enhancement was made with Pearson and Spearman coefficients. The ability of the degree of enhancement to help predict adenocarcinoma (histologic grade, > or =3) was calculated. RESULTS: Histologic-CT colonographic correlation was performed in 29 neoplasms (mean diameter, 27.9 mm; range, 10-65 mm). There was no correlation between size and degree of enhancement, size and histologic grade (R = -0.17, P =.33), or histologic grade and degree of enhancement (R = 0.23, P =.23). However, increasing enhancement was noted between grades 2 and 5. When an enhancement threshold of 40 HU was used for the diagnosis of adenocarcinoma (grades 3-5), sensitivity was 92%, specificity was 20%, positive predictive value was 50%, and negative predictive value was 75%. CONCLUSION: The degree of contrast enhancement on a 45-second-delay CT colonographic image does not correlate with size or degree of histologic differentiation, although increasing enhancement with lesser degrees of differentiation was noted.

Adenocarcinoma↗

PubMed1994

Hepatic CT enhancement. Part II. Alterations in contrast material volume and rate of injection within the same patients.

PURPOSE: To evaluate the effects of alterations in contrast material volume and injection rate on liver computed tomographic (CT) enhancement within the same patients. MATERIALS AND METHODS: Forty patients underwent repeat CT within 6 months, one with 150 mL of nonionic contrast material at 2 mL/sec, the other with 150 mL (n = 8, group A), 100 mL (n = 14, group B), or 180 mL (n = 18, group C) at 3 mL/sec. Comparisons were made only within the same patients. RESULTS: In group A, mean liver enhancement was greater with the higher rate (3 mL/sec) up to 130 seconds after injection, mean peak liver enhancement was greater by 10 HU, and mean time to peak enhancement was shorter by 15 seconds. In group B, mean peak enhancement was greater with 150 mL by 9 HU, and mean time to peak enhancement was longer by 27 seconds. In group C, peak enhancement and time to peak liver enhancement were greater. CONCLUSION: Contrast material volume and injection rate have interdependent effects on liver enhancement and potentially tumor conspicuity. Higher rates compensate partially for lower volume, but enhancement is still reduced. The optimal window of time for imaging after injection varies with injection technique.

Adult↗

PubMed2000

Cartilaginous tumors: fast contrast-enhanced MR imaging.

PURPOSE: To differentiate between benign and malignant cartilaginous tumors with fast contrast material-enhanced magnetic resonance (MR) imaging. MATERIALS AND METHODS: In 37 patients, fast contrast-enhanced MR images were obtained in eight enchondromas, 11 osteochondromas, and 18 chondrosarcomas. Start of enhancement-early, within 10 seconds after arterial enhancement; delayed, between 10 seconds and 2 minutes; late, after 5 minutes on spin-echo images-and progression of enhancement were represented with three types of time-signal intensity curves. Findings were correlated with the surgical specimen in 27 cases, curettage material in three cases, and biopsy combined with long-term follow-up findings in seven cases. RESULTS: Start of enhancement and the combination of start and progression of enhancement correlated significantly (P <.001) with benign and malignant tumors. Early enhancement was seen in chondrosarcoma, not seen in enchondroma, and seen in osteochondroma only when growth plates were unfused. The sensitivity was 89%, specificity 84%, positive predictive value 84%, and negative predictive value 89%. Differentiation of malignancy from benignity on the basis of early and exponential enhancement was possible with a sensitivity of 61%, specificity 95%, positive predictive value 92%, and negative predictive value 72%. CONCLUSION: Preliminary results show that in the adult population fast contrast-enhanced MR imaging may assist in differentiation between benign and malignant cartilaginous tumors.

Adolescent↗

PubMed2000

Hepatic tumors: contrast agent-enhancement patterns with pulse-inversion harmonic US.

PURPOSE: To evaluate contrast agent-enhancement patterns in hepatic hemangiomas, hepatic metastases, and hepatocellular carcinomas (HCCs) at pulse-inversion harmonic ultrasonography (US) with a microbubble contrast agent. MATERIALS AND METHODS: Twenty hepatic hemangiomas in 20 patients and 41 malignant hepatic tumors in 23 patients (33 metastases and eight HCCs) were evaluated with pulse-inversion harmonic US. US images were obtained before injection and every 10-15 seconds after injection of a 4-g bolus (300 mg/mL) of SH U 508A (a microbubble contrast agent) for 5 minutes. The contrast-enhancement patterns of 61 hepatic lesions were assessed. RESULTS: Of 20 hemangiomas, 19 revealed peripheral enhancement, which was globular in 14 (70%) and rimlike in five (25%), with centripetal fill-in; the remaining one (5%) showed homogeneous enhancement. In 33 metastases, the enhancement was rimlike in 16 (48%), homogeneous in seven (21%), and stippled in two (6%); in the remaining eight metastases (24%), no enhancement was seen. Of eight HCCs, four (50%) showed homogeneous enhancement and the remaining four (50%) showed heterogeneous enhancement. Centripetal fill-in of lesions with intratumoral enhancement was not seen in any malignancy. CONCLUSION: Pulse-inversion harmonic US with a microbubble contrast agent is potentially useful for the specific diagnosis of hemangiomas that demonstrate characteristic enhancement features.

Adult↗

PubMed1997

Conserved enhancer elements in human and mouse renin genes have different transcriptional effects in As4.1 cells.

Despite the strong conservation of proximal 5'-flanking DNA sequences, cell transfection and transgenic animal studies have failed to provide a unifying hypothesis to explain the expression of both mouse and human renin genes. Recently, sequences contained in the mouse Ren-1c gene 5'-flanking DNA (-2866 to -2625) were shown to contain an enhancer-like element that stimulates Ren-1c promoter activity in renin-expressing As4.1 cells approximately 80-fold. Earlier studies using transgenic mice had suggested that this same region is required for the cell-specific expression of mouse renin genes. Since existing human renin genomic clones lack sequences homologous to the mouse renin enhancer, we isolated several human P1 and P1 artificial chromosome genomic clones that contain > 80 kb spanning the human renin gene. Analysis of these clones by Southern blot hybridization and long-rang polymerase chain reaction showed that they contain sequences homologous to the mouse enhancer at approximately 12 kb upstream of the transcription start site. Mouse and human sequences were 59% identical over a 650-bp region that contained the minimal enhancer from the mouse Ren-1c gene. However, a 1-kb fragment containing the entire human enhancer homology failed to stimulate human renin promoter activity in transiently transfected As4.1 cells. Further deletional analysis showed that a 220-bp region of the human sequence highly conserved in the mouse Ren-1c gene exhibited up to 47-fold transcriptional stimulation, although this was lower than the maximal effect exhibited by the minimal mouse enhancer (223-fold). Taken together, these observations suggest that sequences surrounding the conserved enhancer core stimulate enhancer activity in the mouse gene but suppress activity in the human gene. The high transcriptional activity of the mouse enhancer may have evolved to support the exceptionally high plasma renin concentrations found in mice. However, the enhancer core and surrounding conserved sequences may play an additional role in directing cell specificity.

Animals↗

PubMed1998

Magnetization transfer ratios in multiple sclerosis lesions enhancing after different doses of gadolinium.

We performed serial monthly magnetization transfer (MT) imaging to evaluate whether MS lesions that enhance only after the injection of a triple dose (TD) of gadolinium-DTPA (Gd) have different pathologic characteristics and evolution than those that enhance after the injection of a standard dose (SD). Every 4 weeks for 3 months and in two separate sessions, we obtained T1-weighted scans from 10 patients with relapsing-remitting MS, 5 minutes after SD (0.1 mmol/kg) or TD (0.3 mmol/kg) Gd injection. During each of the first monthly sessions, we obtained MT images and dual-echo scans before Gd injection. We measured the MT ratio (MTR) of newly enhancing lesions on co-registered quantitative MTR images. During the 3-month follow-up, 81 newly enhancing lesions were seen on SD scans. An additional 46 lesions enhanced only on TD scans. The mean (+/- standard deviation) MTR values were 31.4% +/- 8.4% for lesions enhancing after SD and 38.2% +/- 6.0% for lesions enhancing only after TD injection (p < 0.0001). The mean MTR values of lesions seen with both SD (p < 0.00001) and TD (p = 0.002) increased significantly during the follow-up. At each time point during the follow-up, the MTR values of TD lesions were significantly higher than the SD lesions. These results indicate that the enhancing lesion population in MS is heterogeneous and that the tissue damage occurring within lesions enhancing only after TD injection is less severe than in lesions enhancing after the injection of an SD.

Adult↗

PubMed2005

Convergence of Wnt and FGF signals in the genesis of posterior neural plate through activation of the Sox2 enhancer N-1.

The expression of the transcription factor gene Sox2 precisely marks the neural plate in various vertebrate species. We previously showed that the Sox2 expression prevailing in the neural plate of chicken embryos is actually regulated by the coordination of five phylogenetically conserved enhancers having discrete regional coverage, among which the 420-bp long enhancer N-1, active in the node-proximal region, is probably involved directly in the genesis of the posterior neural plate. We investigated the signaling systems regulating this enhancer, first identifying the 56-bp N-1 core enhancer (N-1c), which in a trimeric form recapitulates the activity of the enhancer N-1. Mutational analysis identified five blocks, A to E, that regulate the enhancer N-1c. Functional analysis of these blocks indicated that Wnt and FGF signals synergistically activate the enhancer through Blocks A-B, bound by Lef1, and Block D, respectively. Fgf8b and Wnt8c expressed in the organizer-primitive streak region account for the activity in the embryo. Block E is essential for the repression of the enhancer N-1c activity in the mesendodermal precursors. The enhancer N-1c is not affected by BMP signals. Thus, Wnt and FGF signals converge to activate Sox2 expression through the enhancer N-1c, revealing the direct involvement of the Wnt signal in the initiation of neural plate development.

Animals↗