Departments of 1 Surgery, 2 Internal Medicine, 3 Pathology, and 5 Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110; and 4 Section of Genetics, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri 64108
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ABSTRACT |
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Members of the forkhead/winged-helix transcription factor family play crucial roles during vertebrate development. A human hepatocyte nuclear factor/forkhead homolog (HFH)-4 cDNA encoding a 421-amino acid protein was isolated from a human fetal lung cDNA library. By Southern blot analysis of human-rodent somatic cell hybrid genomic DNA, the human HFH-4 gene localizes to chromosome 17q23-qter. This is the locus of another forkhead/winged-helix gene, the interleukin enhancer binding factor gene. RNA blot analysis revealed a 2.5-kilobase human HFH-4 transcript in fetal lung, kidney, and brain as well as in adult reproductive tissues, lung, and brain. By in situ hybridization, HFH-4 expression is associated with differentiation of the proximal pulmonary epithelium, starting during the pseudoglandular stage of human lung development. During human renal morphogenesis, HFH-4 is expressed in the developing epithelial cells of the ureteric duct, glomerulus, and epithelial vesicles. The unique pattern of HFH-4 expression during human fetal development suggests a role for this forkhead/winged-helix factor during pulmonary and renal epithelial development.
transcription factors; human development; gene expression
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INTRODUCTION |
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MEMBERS OF THE forkhead/winged-helix family of
transcription factors play important roles in cell-specific gene
expression and cell fate determination (21). Members of this family are characterized by a conserved 100-amino acid DNA-binding domain termed
the forkhead domain or, based on three-dimensional X-ray crystallographic structure, the winged-helix domain (7). These factors
are distributed in a tissue-specific fashion throughout the metazoan
organisms, and multiple family members may be present in a single
organism or cell type (21). The essential role of these transcription
factors during vertebrate development has been demonstrated by targeted
disruption of family member genes. Hepatocyte nuclear factor
(HNF)-3, thymocyte winged helix, brain factor-1, and Mf3 have been
shown to be required for normal patterning in the central nervous
system (1, 10, 22, 39, 42). The multiple roles played by these factors
during vertebrate development are illustrated by targeted disruption of
the HNF-3
gene, which results in disruption of normal foregut
morphogenesis in addition to abnormal central nervous system
development (1, 39). The functional importance of the
forkhead/winged-helix proteins during organogenesis is further
demonstrated by the loss of normal renal tubular development after
disruption of the brain factor-2 gene (16). Additionally, the mouse
nude locus has been
reported to encode a forkhead/winged-helix protein (31). This mutation
results in abnormalities of hair growth and thymic development in
rodents. A homologous protein in humans has not been identified.
The role of the forkhead/winged-helix proteins in the regulation of human development and disease is poorly understood. Although several human forkhead/winged-helix homologs have been identified, their expression during human development has not been well characterized (4, 11, 18, 24, 26, 30, 33). Human chromosomal translocations that result in the formation of forkhead fusion proteins have been associated with malignancies (13, 32, 37). The physiological functions of the proteins involved in these fusions have not been defined as yet. Furthermore, the role of mutations in human forkhead/winged-helix protein genes in the etiology of congenital malformations has not been elucidated.
Hepatocyte nuclear factor/forkhead homolog (HFH)-4 is a recently
identified member of the forkhead/winged-helix family (9, 14). HFH-4 is
expressed in the mouse and rat in a developmentally regulated fashion
in the lung, spermatids, and choroid plexus (9, 14, 27). During mouse
lung development, HFH-4 is expressed exclusively in the proximal
pulmonary epithelium and is associated with differentiation of the
proximal from the distal pulmonary epithelium (14). Recently, a number
of potential target genes for HFH-4 in the pulmonary epithelium have
been identified, including the Clara cell secretory protein gene (CCSP)
and another forkhead/winged-helix gene, HNF-3 (27). In this paper,
the isolation and characterization of a human HFH-4 homolog are
described. Additionally, its patterns of expression in the developing
human lung and kidney are delineated. These patterns of expression
suggest a role for this forkhead/winged-helix protein during human
pulmonary and renal morphogenesis.
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METHODS AND MATERIALS |
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Isolation and characterization of human
HFH-4.
A human fetal (pooled from 20 to 26 wk of gestation) lung
cDNA library (Clontech, Palo Alto, CA) was screened with a 428-base pair (bp) random-primed
[32P]cDNA probe to the
rat HFH-4 forkhead domain. Bacteriophage were plated to a titer of
500,000 plaque-forming units, immobilized on nitrocellulose filter
discs, and hybridized overnight as described (12). Filter discs were
washed and analyzed by autoradiography (12). cDNA inserts were isolated
from the gt11 vector by digestion with
EcoR I and then cloned into
pBluescript II KS(+) (Stratagene, La Jolla, CA). Both strands of
isolated clones were sequenced with either sense or antisense
oligonucleotides using the dideoxy chain termination method of Sanger
et al. (34).
HFH-4 chromosomal mapping. Genomic DNA from the National Institute of General Medical Sciences (NIGMS) Hybrid Mapping Panel No. 2 and from somatic cell hybrids NA-10502, NA-11543, and NA-10659 was obtained from the NIGMS Genetic Mutant Cell Repository (Coriell Institute for Medical Research, Camden, NJ). Mapping Panel No. 2 consists of DNA isolated from human and rodent parental cell lines (mouse and Chinese hamster) and from 24 human-rodent cell hybrids retaining one or two human chromosomes. All but two of the hybrids retain a single human chromosome. The mouse-human somatic cell hybrid line NA-10502 contains a derivative of t(17;19)(q23;p13) and retains 17q23-qter. Cell hybrid NA-11543 contains the human chromosome 17 derivative of t(16;17)(q23;q21) and retains 17q21-qter. Finally, cell hybrid NA-10659 contains the human chromosome derivative of t(15;17)(q22;q11.2) and retains 17q11.2-pter.
Approximately 5 mg of human, hamster, or mouse genomic DNA were digested with BamH I, Hind III, and Pst I to find a suitable restriction fragment length polymorphism for use in mapping. Southern blots were produced and were hybridized with either a 1.4-kilobase (kb) rat HFH-4 cDNA or a 400-bp fragment from the human HFH-4 cDNA as previously described (40).RNA blot analysis. RNA blots containing 2 µg of poly(A)+ RNA isolated from human adult and fetal tissues were obtained from Clontech Laboratories. Blots were hybridized overnight at 42°C with a 216-bp random-primed [32P]cDNA probe from the 5' end of the human HFH-4 cDNA. The HFH-4 probe included 90 bp of the 5'-untranslated region of the human HFH-4 cDNA and up to nucleotide 126 in Fig. 1. After hybridization, blots were washed at increasing stringency in SSC (1× SSC is 0.15 M NaCl and 0.015 M sodium citrate, pH 7.0) with sodium dodecyl sulfate and exposed to autoradiography film for 12-36 h (12).
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In situ hybridization. Human fetal lung and fetal kidney tissue blocks embedded in paraffin were obtained from the Department of Pathology at Washington University School of Medicine (Human Studies Committee Protocol No. 95-0616). Each stage of lung or kidney development was examined with at least two separate tissue blocks. Tissues were deparaffinized in xylene and treated with 10 µg/ml of proteinase K as described previously (15). After treatment with 0.25% (vol/vol) acetic anhydride, sections were dehydrated in ascending concentrations of ethanol. Sections were hybridized overnight with antisense and sense 35S-labeled complementary RNA (cRNA) probes at 62-63°C in the presence of 50 mM dithiothreitol (DTT). For detection of HFH-4 expression, a 383-nucleotide probe encompassing nucleotides 121-503 of the human HFH-4 cDNA was utilized (Fig. 1). Human CCSP expression was detected using a 273-nucleotide full-length human CCSP probe. After hybridization, slides were treated with 20 µg/ml of ribonuclease A and then washed in SSC at increasing stringency, with a final wash in 0.1× SSC at 65°C. DTT was added to wash solutions at a concentration of 5 (lung sections) or 10 mM (kidney sections). After dehydration in ascending concentrations of ethanol (with DTT added as above), sections were exposed to Fuji RX X-ray film to determine appropriate exposure time for liquid autoradiography emulsion. Slides were dipped in Kodak NTB-2 liquid autoradiography emulsion diluted 1:1 with H2O and were exposed for 14-21 days at 4°C as described (15). Slides were developed and counterstained with hematoxylin and eosin. Sections were examined and photographed under bright-field and dark-field illumination.
Probe synthesis.
[32P]cDNA probes for
cDNA library screening and RNA blot analysis were synthesized using the
Prime-It II random-primer labeling kit (Stratagene). Random
oligonucleotide primers were annealed to 25 ng of template DNA,
followed by incubation with
[-32P]dCTP and
unlabeled deoxynucleotides in the presence of Exo(
) Klenow
enzyme. Unincorporated nucleotides were removed with a Nuc-trap column
(Stratagene).
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RESULTS |
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Library screening and cDNA sequence. Screening of a human fetal lung cDNA library with a [32P]cDNA probe to the rat HFH-4 forkhead domain resulted in the identification of five overlapping cDNA clones. Sequence analysis of the isolated clones revealed a 1,497-bp cDNA, homologous to the rat and mouse HFH-4, that was termed human HFH-4. A single open reading frame of 421 amino acids was determined as shown in Fig. 1. The translation start codon is the first in-frame ATG consistent with the Kozak sequence for a translation start codon. A 101-amino acid forkhead domain was identified (shaded region in Fig. 1). The amino acid sequence of human HFH-4 is ~91% identical to the mouse and rat HFH-4 sequences. Within the forkhead domain, the amino acid sequence of the human protein is 100% identical to the rodent proteins.
The overall proline content of the human HFH-4 protein is relatively high (11.2%), and between amino acids 50 and 123, the proline content is 36.4%. Five regions with a high content of negatively charged amino acids were also identified and are underlined in Fig. 1. These regions are from amino acids 15 to 31 (47.1% acidic residues), amino acids 253 to 267 (33.3% acidic residues), amino acids 297 to 323 (29.6% acidic residues), amino acids 364 to 388 (28.6% acidic residues), and amino acids 397 to 413 (29.4% acidic residues).Chromosomal mapping. A human-specific 9.5-kb fragment was identified on Southern blots of BamH I-digested genomic DNA from the parental cell lines (hamster, human, and mouse) when probed with a rat HFH-4 probe (Fig. 2A). Analysis of the Southern blot derived from the Mapping Panel No. 2 genomic DNA indicated that the human-specific 9.5-kb BamH I fragment was observed in cell line 17, which contains an intact human chromosome 17 (Fig. 2A). All other cell hybrids were negative for the human-specific BamH I fragment.
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RNA blot analysis of human HFH-4 expression. RNA blot analysis of adult human poly(A)+ RNA with a random-primed human HFH-4 cDNA probe revealed a 2.5-kb transcript in male and female reproductive tissues (Fig. 3, adult lanes 4 and 5) and lung (Fig. 3, adult lane 12). Prolonged exposure of the adult RNA blot also revealed a 2.5-kb transcript in brain (Fig. 3, adult lane 10) and liver (Fig. 3, adult lane 13). Examination of human fetal tissues revealed a 2.5-kb transcript in brain (pooled sample from 19 to 23 wk of gestation), lung (pooled sample from 22 to 23 wk of gestation), and kidney (pooled sample from 19 to 23 wk of gestation) (Fig. 3, fetal lanes 1, 2, and 4). No HFH-4 transcript was detected in fetal liver (pooled sample from 22 to 26 wk of gestation). Also, despite prolonged exposure of the adult blot, no HFH-4 transcript was ever detected in adult kidney.
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Expression of HFH-4 in human fetal lung. To characterize the pattern of HFH-4 expression during human lung development, in situ hybridization was performed with antisense and sense 35S-cRNA probes to the 5' region of the human HFH-4 cDNA. Examination of embryonic-stage lung tissue from a human fetus at 4 wk of gestation did not reveal any HFH-4 expression (Fig. 4, A and B). By the late-pseudoglandular stage of lung development, at 15 wk of gestation, expression of HFH-4 is noted in the developing proximal bronchiolar epithelium but not in the distal acinar epithelium or surrounding mesenchyme (Fig. 4, C and D). At 21 wk of gestation, during the canalicular stage of lung development, expression of HFH-4 remains confined to the proximal epithelium, with no expression detected in the distal canalicular structures (Fig. 4, E and F). During the saccular stage of lung development, at 28 wk of gestation, HFH-4 expression continues to be restricted to the proximal epithelium of a developing bronchiole, without expression detected in the distal epithelium as it undergoes further alveolarization (Fig. 4, G and H). This same pattern of HFH-4 expression is observed in adult lung tissue, with persistent expression restricted to the proximal respiratory epithelium (data not shown). Hybridization of tissue sections with a sense strand probe was negative (data not shown).
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Expression of HFH-4 in human fetal kidney. Within the developing human kidney at 22 wk of gestation, HFH-4 was expressed in the ureteric duct and the parietal epithelium of the glomerulus (Fig. 6). Within the epithelium of the ureteric duct, transcript was most abundant just proximal to the distal duct tip (Fig. 6, C and D). HFH-4 expression was less prominent in the epithelial cells at the tips of the ureteric ducts and was not detected in the collecting tubules (Fig. 6, A and B). The parietal epithelium of the glomerulus expresses HFH-4, but no expression was detected within the glomerulus itself (Fig. 6, A-D). Occasional expression of HFH-4 was also detected in epithelial vesicles (Fig. 6, A and B). This same pattern of HFH-4 expression was observed within the developing kidney at all gestational ages examined from 4 to 32 wk of gestation (data not shown). No expression of HFH-4 was detected in a control section hybridized with a sense strand HFH-4 probe (Fig. 6, E and F).
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DISCUSSION |
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In this study, a cDNA encoding the human HFH-4 homolog has been identified, and its pattern of expression has been characterized in the developing human lung and kidney. Comparison of the human HFH-4 amino acid sequence with the mouse and rat HFH-4 sequences reveals a high degree of conservation, with >90% amino acid identity throughout the protein and 100% amino acid identity within the DNA-binding forkhead domain (14). Within the amino acid sequence of the HFH-4 protein, a proline-rich NH2-terminal domain and several acidic domains have been identified (Fig. 1). Regions with these characteristics have been identified as transactivating domains in other transcription factors (28). Homologous regions are present in mouse and rat HFH-4 and have recently been shown to confer transactivating activity to the protein (14, 27).
The locus for the human HFH-4 gene maps to chromosome 17q23-qter. These data are consistent with the finding that the mouse hfh-4 gene maps to a region of mouse chromosome 11 homologous to human chromosome 17 (2). The mouse locus is closely linked with P4hb and the fatty acid synthetase locus, which also maps to human 17q25 (2). The human interleukin enhancer binding factor gene, which shares 57% amino acid identity with HFH-4 within the forkhead domain, has also been mapped to human chromosome 17q25 (25). This distal region of chromosome 17q has been identified as a site of translocations in some human acute myelogenous leukemias and chronic lymphoproliferative disorders (29). The genes involved in these translocations as yet remain unidentified. The loci of several other human forkhead/winged-helix genes have also been identified (20, 23, 41). Of these, the human brain factor-1 and -2 genes are linked within the 14q11-13 locus, and the human fkh-6 and MFH-1 homologs are linked within the 16q22-24 locus, similar to the linkage observed for HFH-4 and interleukin enhancer binding factor within 17q23-qter (20, 41). Determination of whether this clustering is a common theme among the human forkhead/winged-helix genes will require the chromosomal localization of additional family members.
Human fetal expression of HFH-4 has been detected in lung, kidney, and brain. Because of the limited nature of the fetal tissues examined, expression elsewhere during human development cannot be excluded. The pattern of HFH-4 expression during human lung development is consistent with a role for HFH-4 in the differentiation of proximal pulmonary epithelial cells. During the pseudoglandular stage of human lung development, respiratory epithelial differentiation occurs that results in the formation of a distal cuboidal and a proximal columnar epithelium (6). The temporal pattern of HFH-4 expression in the proximal pulmonary epithelium during this stage of lung development is unique and suggests a role for this molecule during the earliest stages of differentiation of the proximal epithelium. A similar pattern of HFH-4 expression was observed during mouse lung development (14). Forkhead related activator (FREAC)-1 and -2 are human forkhead proteins also expressed in fetal lung, although the precise temporal and spatial patterns of expression have not been described (33). These two family members, however, are highly homologous to the mouse forkhead protein HFH-8, which is expressed in distal respiratory epithelium (8). Together, these results suggest that these forkhead transcription factors may impart proximal-distal positional information within the developing pulmonary epithelium.
Differentiation implies the activation of cell-specific gene expression
during development. The pattern of HFH-4 expression within the proximal
pulmonary epithelium suggests that it may be involved in the regulation
of cell-specific gene expression in this epithelium. The CCSP gene is a
marker of proximal respiratory epithelial differentiation in a number
of species including humans (15, 19). With consideration of the
technical limitations of using archival tissue, within the developing
human lung, CCSP expression was confined to the proximal epithelium, as
was HFH-4 expression (Fig. 6, C and
D). Within this epithelium, however, CCSP expression was confined to a subset of cells, and HFH-4 expression was detected throughout the proximal epithelium. This same pattern of
CCSP and HFH-4 expression was observed in multiple tissue blocks at a
variety of gestational ages. HFH-4 has been shown recently to activate
transcription through the CCSP promoter in vitro (27). The expression
patterns of the two genes, however, imply that other regulatory factors
in addition to HFH-4 are required for the cell-specific expression of
CCSP. Other forkhead/winged-helix transcription factors, including
HNF-3 and -
and FREAC-1, have also been shown to transactivate
the CCSP promoter in vitro (3, 5, 17, 35, 36). The in vivo functions
and interactions of these proteins in regulating proximal respiratory
epithelial gene expression, however, remain to be delineated.
HFH-4 is expressed in the developing human kidney, and no expression is detectable in adult kidney (Fig. 4). Expression of other winged-helix proteins, including FREAC-3, -4, -5, and -6, has been reported in human fetal kidney, but little is known regarding the pattern of expression of these proteins during renal morphogenesis (33). The pattern of HFH-4 expression during renal development suggests a role for this protein during the development of several epithelial components of the kidney, including the ureteric duct, the parietal epithelium of the glomerulus, and differentiating renal tubules. Another member of the winged-helix family, HFH-11, has recently been reported to be expressed in the metanephric mesenchyme and developing glomerulus and renal tubules in the mouse (43). Additionally, targeted disruption of the mouse winged-helix gene BF-2, expressed in developing kidney stromal cells, results in abnormal epithelial differentiation of the renal tubules (16). BF-2 presumably affects renal epithelial development via interactions between stromal and epithelial cells (16). HFH-4 also appears to function during differentiation of the renal epithelium but, in contrast to BF-2, is expressed within the epithelial cells.
During human fetal development, epithelial cell differentiation is a crucial factor in the development of normal organ function. Expression of the forkhead/winged-helix factor HFH-4 during human fetal development implies an important role for this protein in pulmonary and renal epithelial differentiation. A more precise definition of the function of this protein will require further studies utilizing animal models. Additionally, the role of HFH-4 in human diseases such as developmental anomalies and neoplasia remains to be determined.
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ACKNOWLEDGEMENTS |
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We wish to thank Jonathan D. Gitlin for support and helpful review of the manuscript.
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FOOTNOTES |
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This work was supported by National Institutes of Health Grant R29-HL-52581 (to B. P. Hackett) and a grant from the American Lung Association (S. L. Brody).
Address for reprint requests: B. P. Hackett, Dept. of Pediatrics, Washington Univ. School of Medicine, One Children's Place, St. Louis, MO 63110.
Received 5 September 1997; accepted in final form 5 December 1997.
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