scholarly journals 257.Fibroblast growth factor receptor-1 (FGFR-1) is essential for spermiogenesis and male fertility

2004 ◽  
Vol 16 (9) ◽  
pp. 257
Author(s):  
L. M. Cotton ◽  
G. M. Gibbs ◽  
D. M. De Kretser ◽  
M. K. O'Bryan
Keyword(s):  
Transgenic Mice ◽  
Transgene Expression ◽  
Active Role ◽  
Pi3 Kinase ◽  
Dominant Negative ◽  
Major Constituent ◽  
Sperm Function ◽  
Mrna Levels ◽  
Sperm Tail ◽  
Fgf Signalling

SNTs (Suc-1 associated Neurotrophic Factor Targets) are FGF signalling adaptors and crucial activators of the MAP/PI3 kinase pathways via FGFRs. Screening a rat testis library identified snt-2 as a potential ODF component. ODFs are a major constituent of the sperm tail that we hypothesise play an active role in motility. Using western blot analysis I have localised Fgfr-1 to the sperm tail. As such, I propose that Fgf signalling through snt-2 is involved in sperm tail development/function. To test this hypothesis, I created transgenic mice carrying a dominant-negative variant of Fgfr-1 driven by the protamine 1 promoter (haploid specific). Breeding experiments confirmed males were fertile, although one line showed a tendency towards reduced pup numbers. This effect was strengthened by Daily Sperm Production (DSP), showing significantly reduced DSP (30%↓) compared to wt mice. Transgene expression levels were expressed up to 70 times above native mRNA levels in wt mice; however there was a concurrent up-regulation of the native receptor in transgenic mice. Cumulatively this resulted in only a 6x over-expression in transgene: native mRNA, and illustrated the presence of a feedback mechanism controlling Fgfr-1 expression. To increase transgene expression, I crossed independent lines (double heterozygous, DH) males. Breeding experiments showed males from 1 cross were significantly subfertile (2 v. 10 in wt mice) . DSPs were further reduced, (41%↓) compared to wt mice. Collectively this data shows Fgfr-1 signalling is required for quantitatively normal spermiogenesis, but is also likely to have a post testicular role in sperm function. I hypothesise this is mediated via activation/regulation of motility through the MAP/PI3 kinase pathways. Further, these mouse models provide compelling evidence that infertility in Kallmann's Syndrome patients is composed of both hypothalamic and testicular components. These mice will provide valuable insights into the signal transduction mechanisms controlling sperm function and avenues for contraceptive development.

249. Fibroblast growth factor receptor-1 (FGFR-1) is essential for spermiogenesis, capacitation and male fertility

2005 ◽  
Vol 17 (9) ◽  
pp. 99
Author(s):  
L. M. Cotton ◽  
G. M. Gibbs ◽  
D. M. De Kretser ◽  
M. K. O'Bryan
Keyword(s):  
Transgenic Mice ◽  
Male Fertility ◽  
Transgene Expression ◽  
Surrogate Marker ◽  
Dominant Negative ◽  
Mrna Levels ◽  
Sperm Tail ◽  
Expression Levels ◽  
Over Expression ◽  
Sperm Development

Male infertility is often a result of irregular sperm development/function. The identification of snt-2 (Suc-1 associated Neurotrophic Factor Target 2) and Fgfr-1 to the sperm tail, lead to the hypothesis that Fgf signalling through snt-2 is involved in sperm tail development/function. To test this hypothesis, transgenic mice carrying a dominant-negative variant of Fgfr-1, driven by the protamine 1 promoter (haploid specific) were created. Breeding experiments confirmed male fertility; however, one line was significantly sub-fertile and demonstrated a significantly reduced daily sperm production (DSP, 30%↓). Transgene expression levels were up to 70 times above native mRNA levels in wt mice; however, there was a concurrent upregulation of the native receptor in transgenic mice, resulting in only a 6× over-expression in transgenic:native mRNA. To increase transgene expression, independent lines were crossed (double heterozygous, DH). DH transgene expression levels were up to 120 times above the native mRNA in wild type mice, resulting in a 20× over-expression in transgenic:native mRNA. Breeding experiments showed males from 1 cross were significantly subfertile with DSPs further reduced (41%↓). Collectively this data shows Fgfr-1 signalling is required for quantitatively normal spermiogenesis. Given the millions of sperm that mice produce, a 40%↓ in DSP is unlikely to be responsible for the sub-fertility observed i.e. 2 v. 9 pups/litter. Therefore, a disruption of Fgfr-1 signalling may also induce a post-testicular phenotype. Western blot analysis, using tyrosine phosphorylation as a surrogate marker of sperm capacitation, showed transgenic mice had a significantly attenuated ability to initiate capacitation. As capacitation is an absolute requirement for fertilisation, the absence of capacitating capability is probably the major contributor to the sub-fertility seen in the transgenic mice. This research demonstrates for the first time that the Fgfr-1 signalling cascade is one of several pathways associated with sperm development and function.

scholarly journals Sex Differences in Estrogen-Dependent Transcription of Gonadotropin-Releasing Hormone (GnRH) Gene Revealed in GnRH Transgenic Mice

Endocrinology ◽  
2003 ◽  
Vol 144 (8) ◽  
pp. 3351-3358 ◽  
Author(s):  
Niren R. Thanky ◽  
Ruth Slater ◽  
Allan E. Herbison
Keyword(s):  
Transgenic Mice ◽  
Mrna Expression ◽  
Gene Transcription ◽  
Transgene Expression ◽  
Gonadal Steroids ◽  
Critical Element ◽  
Sexually Dimorphic ◽  
Mrna Levels ◽  
Estrogen Replacement

Abstract The mechanisms through which gonadal steroids exert feedback actions on the activity of the GnRH neurons are not understood. Using a series of GnRH-LacZ transgenic mice we have examined the manner in which gonadal steroids suppress GnRH mRNA expression in male and female mice. The long-term gonadectomy of 5.5-GNZ-3.5 transgenic mice resulted in significant increases in cellular GnRH mRNA expression (P < 0.05) and plasma LH concentrations (P < 0.01) in both sexes. However, cellular levels of LacZ mRNA and β-galactosidase, which provide an index of GnRH gene transcription, were only elevated in males after gonadectomy. This sexually differentiated response was also observed in mice gonadectomized for 2 wk. Estrogen replacement in gonadectomized males returned transgene expression to intact levels. Experiments in transgenic mice with 3′ and 5′ deleted GnRH-LacZ constructs revealed that the suppressive influence of estrogen on LacZ transcription in the male required a critical element located between −5.2 and −1.7 kb of the GnRH promoter. These studies show that the suppression of GnRH mRNA expression by estrogen in the male involves a decrease in GnRH gene transcription that is dependent on a distal GnRH promoter element. The same mechanism does not exist in females, indicating that gonadal steroids suppress GnRH mRNA levels in a sexually dimorphic manner.

Mechanism of monocyte activation and expression of proinflammatory cytochemokines by placenta growth factor

Blood ◽  
2003 ◽  
Vol 102 (4) ◽  
pp. 1515-1524 ◽  
Author(s):  
Suresh K. Selvaraj ◽  
Ranjit K. Giri ◽  
Natalya Perelman ◽  
Cage Johnson ◽  
Punam Malik ◽  
...  
Keyword(s):  
Growth Factor ◽  
Kinase Inhibitor ◽  
Pi3 Kinase ◽  
Dominant Negative ◽  
Mitogen Activated Protein Kinase ◽  
Mrna Levels ◽  
Placenta Growth Factor ◽  
Monocytic Cell ◽  
Monocytic Cell Line ◽  
Activated State

Abstract Monocytes from patients with sickle cell disease (SCD) are in an activated state. However, the mechanism of activation of monocytes in SCD is not known. Our studies showed that placenta growth factor (PlGF) activated monocytes and increased mRNA levels of cytokines (tumor necrosis factor-α [TNF-α] and interleukin-1β [IL-1β]) and chemokines (monocyte chemotactic protein-1 [MCP-1], IL-8, and macrophage inflammatory protein-1β [MIP-1β]) in both normal monocytes and in the THP-1 monocytic cell line. This increase in mRNA expression of cytochemokines was also reflected in monocytes derived from subjects with SCD. We studied the PlGF-mediated downstream cellular signaling events that caused increased transcription of inflammatory cytochemokines and chemotaxis of THP-1 monocytes. PlGF-mediated cytochemokine mRNA and protein expression was inhibited by PD98059 and wortmannin, inhibitors of mitogen-activated protein kinase kinase (MAPK/MEK) kinase and phosphatidylinositol-3 (PI3) kinase, respectively, but not by SB203580, a p38 kinase inhibitor. PlGF caused a time-dependent transient increase in phosphorylation of extracellular signal–regulated kinase-1/2 (ERK-1/2), which was completely inhibited by wortmannin, indicating that activation of PI3 kinase preceded MEK activation. PlGF also induced transient phosphorylation of AKT. MEK and PI3 kinase inhibitors and antibody to Flt-1 abrogated PlGF-induced chemotaxis of THP-1 monocytes. Overexpression of a dominant-negative AKT or a dominant-negative PI3 kinase p85 subunit in THP-1 monocytes attenuated the PlGF-mediated phosphorylation of ERK-1/2, cytochemokine secretion, and chemotaxis. Taken together, these data show that activation of monocytes by PlGF occurs via activation of Flt-1, which results in activation of PI3 kinase/AKT and ERK-1/2 pathways. Therefore, we propose that increased levels of PlGF in circulation play an important role in the inflammation observed in SCD via its effects on monocytes.

scholarly journals Human and Murine Osteocalcin Gene Expression: Conserved Tissue Restricted Expression and Divergent Responses to 1,25-Dihydroxyvitamin D3in Vivo

1997 ◽  
Vol 11 (11) ◽  
pp. 1695-1708 ◽  
Author(s):  
Natalie A. Sims ◽  
Christopher P. White ◽  
Kate L. Sunn ◽  
Gethin P. Thomas ◽  
Melanie L. Drummond ◽  
...  
Keyword(s):  
Gene Expression ◽  
Vitamin D ◽  
Transgenic Mice ◽  
Transgene Expression ◽  
Regulatory Sequences ◽  
Strontium Chloride ◽  
Mrna Levels ◽  
Low Calcium Diet ◽  
Osteocalcin Gene ◽  
Human Osteocalcin

Abstract Human and murine osteocalcin genes demonstrate similar cell-specific expression patterns despite significant differences in gene locus organization and sequence variations in cis-acting regulatory elements. To investigate whether differences in these regulatory regions result in an altered response to 1,25-dihydroxyvitamin D3[ 1,25-(OH)2D3] in vivo, we compared the response of the endogenous mouse osteocalcin gene to a bacterial reporter gene directed by flanking regions of the human osteocalcin gene in transgenic mice. Transgene expression colocalized with endogenous osteocalcin expression in serial sections, being detected in osteoblasts, osteocytes and hypertrophic chondrocytes. In calvarial cell culture lysates from transgenic and nontransgenic mice, the endogenous mouse osteocalcin gene did not respond to 1,25-(OH)2D3 treatment. Despite this, transgene activity was significantly increased in the same cells. Similarly, Northern blots of total cellular RNA and in situ hybridization studies of transgenic animals demonstrated a maximal increase in transgene expression at 6 h after 1,25-(OH)2D3 injection (23.6 ± 3.6-fold) with a return to levels equivalent to uninjected animals by 24 h (1.2 ± 0.1-fold). This increase in transgene expression was also observed at 6 h after 1,25-(OH)2D3 treatment in animals on a low calcium diet (25.2 ± 7.7-fold) as well as in transgenic mice fed a vitamin D-deficient diet containing strontium chloride to block endogenous 1,25-(OH)2D3 production (7.5 ± 0.9-fold). In contrast to the increased transgene expression levels, neither endogenous mouse osteocalcin mRNA levels nor serum osteocalcin levels were significantly altered after 1,25-(OH)2D3 injection in transgenic or nontransgenic mice, regardless of dietary manipulations, supporting evidence for different mechanisms regulating the response of human and mouse osteocalcin genes to 1,25-(OH)2D3. Although the cis- and trans-acting mechanisms directing cell-specific gene expression appear to be conserved in the mouse and human osteocalcin genes, responsiveness to 1,25-(OH)2D3 is not. The mouse osteocalcin genes do not respond to 1,25-(OH)2D3 treatment, but the human osteocalcin-directed transgene is markedly up-regulated under the same conditions and in the same cells. The divergent responses of these homologous genes to 1,25-(OH)2D3 are therefore likely to be due to differences in mouse and human osteocalcin-regulatory sequences rather than to variation in the complement of trans-acting factors present in mouse osteoblastic cells. Increased understanding of these murine-human differences in osteocalcin regulation may shed light on the function of osteocalcin and its regulation by vitamin D in bone physiology.

In vivo expression profile of a H+-K+-ATPase α2-subunit promoter-reporter transgene

2004 ◽  
Vol 286 (6) ◽  
pp. F1171-F1177 ◽  
Author(s):  
Wenzheng Zhang ◽  
Xuefeng Xia ◽  
Lei Zou ◽  
Xiangyang Xu ◽  
Gene D. LeSage ◽  
...  
Keyword(s):  
Fluorescence Microscopy ◽  
Transgenic Mice ◽  
Reporter Gene ◽  
Transgene Expression ◽  
Fluorescent Protein ◽  
Collecting Duct ◽  
Distal Colon ◽  
Mrna Levels ◽  
Flanking Region

Because little is known about the molecular basis of transcriptional regulation of the murine H+-K+-ATPase α2 (HKα2) gene or other genes whose expression is restricted in part to the collecting duct, especially in vivo, we developed transgenic mice carrying an insertional HKα2 promoter-reporter gene construct. In these mice, the region −7,264/+253 of the HKα2 5′-flanking region controls expression of the reporter gene enhanced green fluorescent protein (EGFP). Patterns of HKα2/EGFP transgene expression were examined by fluorescence microscopy and immunoblotting. Of 10 major organs examined, EGFP immunoreactivity was detected abundantly in the kidney, and to a far lesser extent, in the brain and lung. Within the kidney, EGFP fluorescence was detected exclusively in the collecting ducts of transgenic mice and colocalized with the cellular distribution of both endogenous HKα2 and aquaporin-2, consistent with the known expression pattern of endogenous HKα2 in principal cells. Surprisingly, no transgene expression was evident by immunoblotting or fluorescence microscopy in the distal colon, the site of the highest endogenous HKα2 expression. Although previous studies of steady-state mRNA levels suggested differences in HKα2 gene regulation in the kidney and colon, our results provide the first direct evidence of differential transcriptional control of the HKα2 gene in these organs and suggest that regions outside the 5′-flanking region or other regulatory factors play a role in HKα2 expression in the distal colon.

scholarly journals Cellular Werner Phenotypes in Mice Expressing a Putative Dominant-Negative Human WRN Gene

Genetics ◽  
2000 ◽  
Vol 154 (1) ◽  
pp. 357-362
Author(s):  
Lan Wang ◽  
Charles E Ogburn ◽  
Carol B Ware ◽  
Warren C Ladiges ◽  
Hagop Youssoufian ◽  
...  
Keyword(s):  
Mouse Model ◽  
Transgenic Mice ◽  
Werner Syndrome ◽  
Dominant Negative ◽  
Dominant Negative Mutation ◽  
Fibroblast Cultures ◽  
Age Related

Abstract Mutations at the Werner helicase locus (WRN) are responsible for the Werner syndrome (WS). WS patients prematurely develop an aged appearance and various age-related disorders. We have generated transgenic mice expressing human WRN with a putative dominant-negative mutation (K577M-WRN). Primary tail fibroblast cultures from K577M-WRN mice showed three characteristics of WS cells: hypersensitivity to 4-nitroquinoline-1-oxide (4NQO), reduced replicative potential, and reduced expression of the endogenous WRN protein. These data suggest that K577M-WRN mice may provide a novel mouse model for the WS.

scholarly journals Targeting fibroblast growth factor receptors to combat aggressive ependymoma

2021 ◽  
Author(s):  
Daniela Lötsch ◽  
Dominik Kirchhofer ◽  
Bernhard Englinger ◽  
Li Jiang ◽  
Konstantin Okonechnikov ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Molecular Mechanisms ◽  
Radial Glia ◽  
Growth Factor Receptors ◽  
Dominant Negative ◽  
Mrna Levels ◽  
Fibroblast Growth ◽  
Cell Models ◽  
Fibroblast Growth Factor Receptors

AbstractEpendymomas (EPN) are central nervous system tumors comprising both aggressive and more benign molecular subtypes. However, therapy of the high-risk subtypes posterior fossa group A (PF-A) and supratentorial RELA-fusion positive (ST-RELA) is limited to gross total resection and radiotherapy, as effective systemic treatment concepts are still lacking. We have recently described fibroblast growth factor receptors 1 and 3 (FGFR1/FGFR3) as oncogenic drivers of EPN. However, the underlying molecular mechanisms and their potential as therapeutic targets have not yet been investigated in detail. Making use of transcriptomic data across 467 EPN tissues, we found that FGFR1 and FGFR3 were both widely expressed across all molecular groups. FGFR3 mRNA levels were enriched in ST-RELA showing the highest expression among EPN as well as other brain tumors. We further identified high expression levels of fibroblast growth factor 1 and 2 (FGF1, FGF2) across all EPN subtypes while FGF9 was elevated in ST-EPN. Interrogation of our EPN single-cell RNA-sequencing data revealed that FGFR3 was further enriched in cycling and progenitor-like cell populations. Corroboratively, we found FGFR3 to be predominantly expressed in radial glia cells in both mouse embryonal and human brain datasets. Moreover, we detected alternative splicing of the FGFR1/3-IIIc variant, which is known to enhance ligand affinity and FGFR signaling. Dominant-negative interruption of FGFR1/3 activation in PF-A and ST-RELA cell models demonstrated inhibition of key oncogenic pathways leading to reduced cell growth and stem cell characteristics. To explore the feasibility of therapeutically targeting FGFR, we tested a panel of FGFR inhibitors in 12 patient-derived EPN cell models revealing sensitivity in the low-micromolar to nano-molar range. Finally, we gain the first clinical evidence for the activity of the FGFR inhibitor nintedanib in the treatment of a patient with recurrent ST-RELA. Together, these preclinical and clinical data suggest FGFR inhibition as a novel and feasible approach to combat aggressive EPN.

scholarly journals The CD11b promoter directs high-level expression of reporter genes in macrophages in transgenic mice [published erratum appears in Blood 1995 Apr 1;85(7):1983]

Blood ◽  
1995 ◽  
Vol 85 (2) ◽  
pp. 319-329 ◽  
Author(s):  
S Dziennis ◽  
RA Van Etten ◽  
HL Pahl ◽  
DL Morris ◽  
TL Rothstein ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transgenic Mice ◽  
Transgene Expression ◽  
Heterologous Gene Expression ◽  
Myeloid Cells ◽  
Reporter Genes ◽  
Regulatory Elements ◽  
Specific Expression ◽  
High Level

Abstract CD11b is the alpha chain of the Mac-1 integrin and is preferentially expressed in myeloid cells (neutrophils, monocytes, and macrophages). We have previously shown that the CD11b promoter directs cell-type- specific expression in myeloid lines using transient transfection assays. To confirm that these promoter sequences contain the proper regulatory elements for correct myeloid expression of CD11b in vivo, we have used the -1.7-kb human CD11b promoter to direct reporter gene expression in transgenic mice. Stable founder lines were generated with two different reporter genes, a Thy 1.1 surface marker and the Escherichia coli lacZ (beta-galactosidase) gene. Analysis of founders generated with each reporter demonstrated that the CD11b promoter was capable of driving high levels of transgene expression in murine macrophages for the lifetime of the animals. Similar to the endogenous gene, transgene expression was preferentially found in mature monocytes, macrophages, and neutrophils and not in myeloid precursors. These experiments indicate that the -1.7 CD11b promoter contains the regulatory elements sufficient for high-level macrophage expression. This promoter should be useful for targeting heterologous gene expression to mature myeloid cells.

Interactions of insulin-like growth factor (IGF)-II and growth hormone in vivo: circulating levels of IGF-I and IGF-binding proteins in transgenic mice

1997 ◽  
pp. 701-708 ◽  
Author(s):  
A Blackburn ◽  
RA Dressendorfer ◽  
WF Blum ◽  
M Erhard ◽  
G Brem ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Transgene Expression ◽  
High Protein Diet ◽  
High Protein ◽  
Protein Diet ◽  
Standard Diet ◽  
Igf I ◽  
Igf Binding ◽  
B Mice

To study interactions between insulin-like growth factor-II (IGF-II) and growth hormone (GH) in vivo, we crossed hemizygous transgenic mice carrying phosphoenolpyruvate carboxykinase (PEPCK)-IGF-II fusion genes with hemizygous PEPCK-bovine GH (bGH) transgenic mice. Offspring harbouring both transgenes (IB), the IGF-II transgene (I) or the bGH transgene (B), and non-transgenic littermates (C) were obtained. Blood samples were taken before (end of week 12) and after (end of week 14) the mice had received a diet high in protein and low in carbohydrates to stimulate PEPCK promoter-controlled transgene expression. Mean serum GH concentrations of both B and IB mice corresponded to 900 ng/ml and increased more than twofold (P < 0.001) after 1 week of the high-protein diet. GH concentrations in controls and I mice were less than 20 ng/ml. Serum IGF-II concentrations in I and IB mice were three-to fourfold higher than those in C and B mice. Whereas IGF-II concentrations were not changed by the high-protein diet in the last two groups, serum IGF-II increased significantly in I (P < 0.001) and IB mice (P < 0.05). This increase was significantly (P < 0.05) less pronounced in IB than in C and I mice. Circulating IGF-I concentrations were about twofold (P < 0.001) higher in B and IB than in C and I mice, and showed a tendency to be lower in I than in C and in IB than in B mice when animals were maintained on the standard diet. The high-protein diet did not change circulating IGF-I concentrations in controls and B mice, but resulted in a significant reduction of serum IGF-I concentrations in I (P < 0.05) and IB mice (P < 0.001). Consequently, after PEPCK-IGF-II transgene expression was stimulated, serum IGF-I concentrations were significantly (P < 0.05) lower in I than in C and in IB than in B mice. Serum IGF-binding protein (IGFBP)-2 concentrations were significantly (P < 0.05) higher in I mice than in all other groups when mice were maintained on the standard diet, with a tendency to reduced IGFBP-2 concentrations in B mice. After the high-protein diet, serum IGFBP-2 concentrations did not change in C and I mice, but increased by two- to threefold in B and IB mice (P < 0.001). Serum IGFBP-3 concentrations tended to be greater in B and IB than in C and I mice, but these differences were mostly not significant. IGFBP-4 concentrations were significantly (P < 0.001) increased by GH overproduction in B and IB mice. Our data suggest that the reduction in circulating IGF-I concentrations by increased IGF-II is most probably due to the limited serum IGF binding capacity and the short half-life of free IGFs, rather than to a reduction in GH-dependent IGF-I production. Effects of GH overproduction on serum IGFBP-2 concentrations depend on dietary factors and may be both inhibitory and stimulatory.

scholarly journals Intestinal Apolipoprotein A-IV Gene Transcription Is Controlled by Two Hormone-Responsive Elements: A Role for Hepatic Nuclear Factor-4 Isoforms

2005 ◽  
Vol 19 (9) ◽  
pp. 2320-2334 ◽  
Author(s):  
Amena Archer ◽  
Dominique Sauvaget ◽  
Valérie Chauffeton ◽  
Pierre-Etienne Bouchet ◽  
Jean Chambaz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transgenic Mice ◽  
Distal Region ◽  
Proximal Region ◽  
Dominant Negative ◽  
Specific Expression ◽  
Nuclear Factors ◽  
Dominant Negative Form ◽  
Responsive Element ◽  
Hormone Responsive Element

Abstract In the small intestine, the expression of the apolipoprotein (apo) C-III and A-IV genes is restricted to the enterocytes of the villi. We have previously shown that, in transgenic mice, specific expression of the human apo C-III requires a hormone-responsive element (HRE) located in the distal region of the human apoA-IV promoter. This HRE binds the hepatic nuclear factors (HNF)-4α and γ. Here, intraduodenal injections in mice and infections of human enterocytic Caco-2/TC7 cells with an adenovirus expressing a dominant-negative form of HNF-4α repress the expression of the apoA-IV gene, demonstrating that HNF-4 controls the apoA-IV gene expression in enterocytes. We show that HNF-4α and γ functionally interact with a second HRE present in the proximal region of the human apoA-IV promoter. New sets of transgenic mice expressing mutated forms of the promoter, combined with the human apo C-III enhancer, demonstrate that, whereas a single HRE is sufficient to reproduce the physiological cephalo-caudal gradient of apoA-IV gene expression, both HREs are required for expression that is restricted to villi. The combination of multiple HREs may specifically recruit regulatory complexes associating HNF-4 and either coactivators in villi or corepressors in crypts.

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