Transcriptional hierarchy in Xenopus embryogenesis: HNF4 a maternal factor involved in the developmental activation of the gene encoding the tissue specific transcription factor HNF1α (LFB1)

Holewa, Beatrix; Strandmann, Elke Pogge von; Zapp, D; Lorenz, Petra; Ryffel, Gerhart U.

doi:10.1016/0925-4773(95)00460-2

Cited by 39 publications

(41 citation statements)

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“…Using this model we have shown previously that the Xenopus HNF1␣ promoter contains an HNF1-binding site (26). By injecting synthetic RNA encoding human HNF1␣ or HNF1␤ into fertilized Xenopus eggs, we observed in the late gastrula an activation of the endogenous HNF1␣ gene (Fig.…”

Section: Resultsmentioning

confidence: 99%

The mutated human gene encoding hepatocyte nuclear factor 1β inhibits kidney formation in developing Xenopus embryos

Wild

Strandmann

Nastos

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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The transcription factor hepatocyte nuclear factor 1␤ (HNF1␤) is a tissue-specific regulator that also plays an essential role in early development of vertebrates. In humans, four heterozygous mutations in the HNF1␤ gene have been identified that lead to early onset of diabetes and severe primary renal defects. The degree and type of renal defects seem to depend on the specific mutation. We show that the frameshift mutant P328L329fsdelCCTCT associated with nephron agenesis retains its DNA-binding properties and acts as a gain-of-function mutation with increased transactivation potential in transfection experiments. Expression of this mutated factor in the Xenopus embryo leads to defective development and agenesis of the pronephros, the first kidney form of amphibians. Very similar defects are generated by overexpressing in Xenopus the wild-type HNF1␤, which is consistent with the gain-of-function property of the mutant. In contrast, introduction of the human HNF1␤ mutant R137-K161del, which is associated with a reduced number of nephrons with hypertrophy of the remaining ones and which has an impaired DNA binding, shows only a minor effect on pronephros development in Xenopus. Thus, the overexpression of both human mutants has a different effect on renal development in Xenopus, reflecting the variation in renal phenotype seen with these mutations. We conclude that mutations in human HNF1␤ can be functionally characterized in Xenopus. Our findings imply that HNF1␤ not only is an early marker of kidney development but also is functionally involved in morphogenetic events, and these processes can be investigated in lower vertebrates.

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Section: Resultsmentioning

confidence: 99%

The mutated human gene encoding hepatocyte nuclear factor 1β inhibits kidney formation in developing Xenopus embryos

Wild

Strandmann

Nastos

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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“…Recently, novel human and Xenopus HNF4 isoforms (HNF4␥ and HNF4␤, respectively) have been identified and shown to be derived from two distinct and differentially expressed genes (14,24). HNF4 is expressed very early during embryo development and has been found to be a crucial positive-acting factor for the expression of the HNF1 gene (55), placing HNF4 at the top of a transactivator hierarchy in hepatic cells (23,36). Disruption of the HNF4␣ gene led to early embryonic death due to malfunction of the yolk sac (7).…”

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Protein Kinase A-Dependent Phosphorylation Modulates DNA-Binding Activity of Hepatocyte Nuclear Factor 4

Viollet

Kahn

Raymondjean

1997

Molecular and Cellular Biology

179

163

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Hepatocyte nuclear factor 4 (HNF4), a liver-enriched transcription factor of the nuclear receptor superfamily, is critical for development and liver-specific gene expression. Here, we demonstrate that its DNAbinding activity is modulated posttranslationally by phosphorylation in vivo, ex vivo, and in vitro. In vivo, HNF4 DNA-binding activity is reduced by fasting and by inducers of intracellular cyclic AMP (cAMP) accumulation. A consensus protein kinase A (PKA) phosphorylation site located within the A box of its DNA-binding domain has been identified, and its role in phosphorylation-dependent inhibition of HNF4 DNA-binding activity has been investigated. Mutants of HNF4 in which two potentially phosphorylatable serines have been replaced by either neutral or charged amino acids were able to bind DNA in vitro with affinity similar to that of the wild-type protein. However, phosphorylation by PKA strongly repressed the binding affinity of the wild-type factor but not that of HNF4 mutants. Accordingly, in transfection assays, expression vectors for the mutated HNF4 proteins activated transcription more efficiently than that for the wild-type protein when cotransfected with the PKA catalytic subunit expression vector. Therefore, HNF4 is a direct target of PKA which might be involved in the transcriptional inhibition of liver genes by cAMP inducers.The liver-enriched transcription factor hepatocyte nuclear factor 4 (HNF4) (54) is involved in close association with other factors in hormonal and dietary control of liver and intestine genes. In addition, HNF4 has a potential role as a developmental regulator that has been conserved during evolution from invertebrates to vertebrates. HNF4 expression is restricted to the liver, kidney, and intestine (60) and, in Drosophila melanogaster, to the malpighian tubules (61). HNF4 exists as various isoforms. At least five different cDNAs are generated by differential splicing from a single gene, the HNF4␣ gene, in the amino-and carboxy-terminal regions; in all isoforms the DNA-binding domain remains unchanged (6,14,20,33,53,54). Recently, novel human and Xenopus HNF4 isoforms (HNF4␥ and HNF4␤, respectively) have been identified and shown to be derived from two distinct and differentially expressed genes (14,24). HNF4 is expressed very early during embryo development and has been found to be a crucial positive-acting factor for the expression of the HNF1 gene (55), placing HNF4 at the top of a transactivator hierarchy in hepatic cells (23,36). Disruption of the HNF4␣ gene led to early embryonic death due to malfunction of the yolk sac (7).HNF4 is a member of the nuclear receptor superfamily that binds to DNA at direct repeats separated by one nucleotide (DR1). This transactivator preexists as very stable homodimers in solution, and no HNF4-specific ligand has been identified so far (27). Therefore, HNF4 is classified as an orphan nuclear receptor, characterized by two zinc finger DNA-binding motifs, a large conserved hydrophobic domain containing the dimerization, and a putative ...

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“…Surprisingly, in early Xenopus embryogenesis, HNF1␣ transcription is very low (1, 26), although the transcription factors HNF4␣ and HNF4␤ are abundantly present (12,13). In addition, the HNF4 proteins are distributed in a gradient from the animal to the vegetal pole, with the highest concentration in the animal region that does not differentiate into tissues expressing the target gene HNF1␣ (12,29). The discrepancy between the presence of the transcription factor HNF4 and the inactivity of its target gene HNF1␣ might now be explained by our finding that a novel component in the Xenopus embryo inhibits the DNA-binding activity of HNF4.…”

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“…In addition to its role as a tissue-specific transcription factor, HNF4␣ is also a maternal component in the egg of Drosophila melanogaster (46) as well as of the amphibian species Xenopus laevis (12). In the mouse, an early embryonic function is implied by the fact that HNF4␣ transcripts are present in the primary endoderm at day 4.5 (6) and can be detected in totipotent embryonic stem cells (25).…”

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“…Both proteins (12) are believed to contribute to the zygotic activation of the gene encoding HNF1␣, a distinct tissue-specific transcription factor of the homeodomain family. Consistent with this assumption, we have identified a functional HNF4 binding site in the HNF1␣ promoter (12,13,30). Furthermore, overexpression of HNF4␣ or HNF4␤ in Xenopus embryos leads to a dramatic increase in expression of the endogenous HNF1␣ gene as early as the late blastula stage (26).…”

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Inhibitor of the Tissue-Specific Transcription Factor HNF4, a Potential Regulator in Early Xenopus Development

Peiler

Böckmann

Nakhei

et al. 2000

Molecular and Cellular Biology

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Hepatocyte nuclear factor 4␣ (HNF4␣) is an orphan receptor of the nuclear receptor superfamily and expressed in vertebrates as a tissue-specific transcription factor in liver, kidney, intestine, stomach, and pancreas. It also plays a crucial role in early embryonic development and has been identified as a maternal component in the Xenopus egg. We now report on an activity present in Xenopus embryos that inhibits the DNA binding of HNF4. This HNF4 inhibitor copurifies with a 25-kDa protein under nondenaturing conditions but can be separated from this protein by sodium dodecyl sulfate treatment. Protease treatment of the inhibitor results in a core fragment of about 5 kDa that retains full inhibitory activity. The activity of the HNF4 inhibitor can also be monitored in the absence of DNA, as it alters the mobility of the HNF4 protein in native polyacrylamide gels and the accessibility of antibodies. Comparing the activity of the HNF4 inhibitor with acyl coenzyme A's, recently proposed to be ligands of HNF4, we observe a more stringent specificity for the HNF4 inhibitor activity. Using deletion constructs of the HNF4 protein, we could show that the potential ligandbinding domain of HNF4 is not required, and thus the HNF4 inhibitor does not represent a classical ligand as defined for the nuclear receptor superfamily. Based on our previous finding that maternal HNF4 is abundantly present in Xenopus embryos but the target gene HNF1␣ is only marginally expressed, we propose that the HNF4 inhibitor functions in the embryo to restrict the activity of the maternal HNF4 proteins.Hepatocyte nuclear factor 4 (HNF4) constitutes transcription factor subfamily 2A (28), whose first member, HNF4␣ (NR2A1), has been identified as a factor interacting with promoter elements mediating liver-specific transcription (35). Based on the zinc finger motif of the DNA-binding domain and on a potential ligand-binding domain, HNF4 is classified as a member of the nuclear orphan receptor superfamily (33). Recently, it has been reported that acyl coenzyme A's (acylCoAs) are potential ligands of HNF4␣: acyl-CoAs containing fatty acids with 16 C residues or shorter act as agonists by increasing the DNA-binding potential of HNF4␣, whereas acyl-CoAs with 18 C residues or longer have antagonistic properties and inhibit DNA binding of HNF4␣ (11). HNF4␣ turned out to be present as well in nonhepatic cells such as kidney, intestine, stomach, and pancreas (23,38,45). The importance of HNF4␣ in gene control in tissues distinct from the liver has been documented by the fact that an inherited human disease is based on the expression of a mutated HNF4␣ gene in the ␤ cells of the endocrine pancreas, leading to maturity-onset diabetes of the young (MODY1 [42]). Most interestingly, another MODY gene identified in humans represents the tissuespecific transcription factor HNF1␣ (43), known to be tightly regulated by HNF4 (17,39,44).In addition to its role as a tissue-specific transcription factor, HNF4␣ is also a maternal component in the egg of Drosophila melano...

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Transcriptional hierarchy in Xenopus embryogenesis: HNF4 a maternal factor involved in the developmental activation of the gene encoding the tissue specific transcription factor HNF1α (LFB1)

Cited by 39 publications

References 38 publications

The mutated human gene encoding hepatocyte nuclear factor 1β inhibits kidney formation in developing Xenopus embryos

The mutated human gene encoding hepatocyte nuclear factor 1β inhibits kidney formation in developing Xenopus embryos

Protein Kinase A-Dependent Phosphorylation Modulates DNA-Binding Activity of Hepatocyte Nuclear Factor 4

Inhibitor of the Tissue-Specific Transcription Factor HNF4, a Potential Regulator in Early Xenopus Development

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