Human Molecular Genetics, 2000, Vol. 9, No. 3 413-419
© 2000 Oxford University Press
Mice deficient in the candidate tumor suppressor gene Hic1 exhibit developmental defects of structures affected in the Miller–Dieker syndrome
1Graduate Program in Human Genetics and Molecular Biology, 2Graduate Program in Cellular and Molecular Medicine, 3Division of Comparative Medicine, 4Department of Pathology and 5Department of Molecular Microbiology and Immunology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA, 6Transgenic and Knockout Facility, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224-6825, USA, 7The Oncology Center, The Johns Hopkins Medical Institutions, 424 North Bond Street, Baltimore, MD 21231, USA
Received 15 October 1999; Revised and Accepted 7 December 1999.
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ABSTRACT |
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HIC1 is a candidate tumor suppressor gene which is frequently hypermethylated in human tumors, and its location within the Miller–Dieker syndrome’s critical deletion region at chromosome 17p13.3 makes it a candidate gene for involvement in this gene deletion syndrome. To study the function of murine Hic1 in development, we have created Hic1-deficient mice. These animals die perinatally and exhibit varying combinations of gross developmental defects throughout the second half of development, including acrania, exencephaly, cleft palate, limb abnormalities and omphalocele. These findings demonstrate a role for Hic1 in the development of structures affected in the Miller–Dieker syndrome, and provide functional evidence to strengthen its candidacy as a gene involved in this disorder.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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HIC1 is a pox virus zinc-finger (POZ) domain-containing zinc-finger transcription factor and candidate tumor suppressor gene (1–7) which resides at chromosome 17p13.3, a region frequently deleted in most common human cancers (8–14). Previously, we and others have shown that there is frequent hypermethylation and lack of expression of this gene in multiple tumor types (1,3,5). Human tumor cells appear to tolerate insertion of exogenous HIC1 poorly (1). Its location within the 350 kb critical region deleted in most patients with the Miller–Dieker syndrome (MDS; OMIM 247200) (1,15,16) makes HIC1 one of several candidate genes for involvement in MDS. Although the lissencephaly and mental retardation seen in MDS has been attributed to LIS1 haploinsufficiency (17–20), MDS patients have other developmental anomalies, including craniofacial dysmorphology, defects of the limbs and digits, and omphalocele (21,22). These features of this complex, variable phenotype are thought to be due to deletion of genes distal to LIS1 in the MDS critical region (22,23). To address the question of a developmental role for HIC1, we have created Hic1-deficient mice and characterized them in terms of embryonic and neonatal viability, gross developmental abnormalities and histological structure.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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By comparing murine Hic1 sequences to the human homolog (GenBank accession nos AF036582 and L41919, respectively), we identified a single 2.6 kb exon containing the entire coding region (Fig. 1a). This open reading frame was verified through in vitro transcription and translation of genomic clones (data not shown). Comparison of the human HIC1 and murine Hic1 coding regions demonstrates 88 and 95% identity at the nucleotide and amino acid levels, respectively. Alignment of Hic1 genomic and expressed sequence tag (EST) sequences (GenBank accession nos AA103371 and AA118648) revealed expression from two alternate promoters, each with its own 5'-untranslated region and splice donor site (Fig. 1a). Expression and splicing of these transcripts were confirmed in adult mouse tissues and human tumor cell lines by reverse transcription–polymerase chain reaction (RT–PCR) and sequencing (data not shown).
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Northern blot studies of mouse embryos show that Hic1 transcripts from both promoters appear prominently in whole mouse embryo mRNA from embryonic day 7 to 17 (E7–E17) (data not shown). Adult mouse tissues show ubiquitous expression, with the most abundant expression observed in heart and lung. Similar expression levels are seen for each exon, with a second, larger transcript detected by the exon 1b probe.
Homologous recombination in embryonic stem (ES) cells was employed to delete the entire Hic1 coding region (Fig. 1b). Twenty matings of F1 hybrid Hic1+/– animals produced 107 pups, and genotypic analysis at weaning age indicated that Hic1–/– animals were completely absent (Table 1). Embryos were harvested from 16 F1 hybrid Hic1+/– matings, and genotypic analysis of the 103 embryos showed the presence of Hic1–/– embryos throughout the second half of development (Table 1). No Hic1 transcripts were detected in whole embryo total RNA of Hic1–/– embryos by RT–PCR, whereas wild-type and Hic1+/– embryos had easily detectable Hic1 transcripts (Fig. 2c). Direct observation of births revealed that Hic1–/– pups are stillborn.
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Of the 20 Hic1–/– embryos harvested, 9 from stage E12.5 to E18.5 exhibited a range of gross developmental defects (Table 2), whereas no such abnormalities were observed in Hic1+/+ or Hic1+/– embryos. First, a reduction in overall size was seen in some Hic1–/– embryos. For example, one Hic1–/– embryo harvested at E12.5 had a crown-rump (CR) distance of 3.8 mm, whereas that of its Hic1+/+ littermate was 5.0 mm. Its immature appearance suggests a global developmental delay (Fig. 3a). Abnormal Hic1–/– embryos harvested at E14.5 had CR distances of 7.1 and 6.1 mm, compared with 9.0 mm for a Hic1+/+ littermate (Fig. 3b). At E18.5, a Hic1–/– embryo had a CR distance of 9.8 mm, making it approximately half the size of its wild-type littermate (18 mm) (Fig. 3f). This diminished overall size was seen only in Hic1–/– embryos with profound defects, suggesting that such stunting may be secondary to the major developmental abnormalities.
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Secondly, some Hic1–/– embryos exhibited defects in craniofacial development. One E14.5 Hic1–/– embryo failed to develop a left eye, whereas its right eye appeared normal, and its left ear was less developed and positioned lower on the head than that of its Hic1+/+ littermate (Fig. 3b). Another Hic1–/– embryo in the same litter showed profound craniofacial defects resembling the holo- prosencephaly reported in Shh-deficient mice (24), with a single fused eyespot under a proboscis-like protrusion of the telencephalon, as well as a failure of the mandibular arches and maxillary processes to fuse at the midline (Fig. 3b). Acrania and exencephaly were observed in two Hic1–/– embryos (E15.5, Fig. 3d; E16.5, Fig. 3e and g), and histologic examination showed an absence of overlying dura mater (Fig. 4d), which gives rise to cranial bones. Compared with control embryos, these individuals had shorter snouts and ears which were less developed and positioned lower on the head. One was also missing its right eyespot, with visible hemorrhages in the exposed brain tissue (Fig. 3e and g). At E18.5, one Hic1–/– embryo exhibited exencephaly with profound disruption of development in the brain and its supporting structures (Figs 3f and 4c). Abnormalities in development and closure of the secondary palate were also seen. In E18.5 littermates, although some rugae have formed in the Hic1–/– embryo, the secondary palate is truncated compared with a Hic1+/+ littermate, with an opening into the nasal cavity (Fig. 4a and b). These findings suggest that Hic1 may play a role in craniofacial development. Patients with MDS have a characteristic facial appearance, which includes bitemporal hollowing, hypertelorism with a broad nasal bridge, low-set ears and an upturned nose, suggesting that one or more genes within the critical deletion region play a role in craniofacial development (21,23).
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A third feature seen in some of the abnormal Hic1–/– embryos was limb and digit dysmorphology. At E15.5, the hind limbs and digits of one Hic1–/– embryo were smaller and markedly different from a Hic1+/+ littermate (Fig. 3c), and the hind limb of an E18.5 Hic1–/– embryo was similarly deformed (Fig. 3f). More subtle differences were seen at E15.5, with thinner forelimbs and abnormal position of the elbow and patella in one Hic1–/– individual (Fig. 3c and d). Although the limb and digit abnormalities reported here in Hic1–/– embryos may not be an exact match with those seen in MDS patients (camptodactyly, clinodactyly, polydactyly) (25), they do suggest a role for Hic1 in limb and/or digit development.
Finally, ventral body wall defects were seen in Hic1–/– embryos. During normal development, the elongating midgut migrates out into the body stalk until the abdominal cavity expands. It returns to the body cavity, folding and rotating into position behind and under the transverse colon. The ventral body wall is fused at ~E16.5 (26). A Hic1–/– embryo at E18.5 had a ventral body wall defect resembling the physiological umbilical hernias seen earlier in development, with loops of intestine clearly visible outside of the body cavity (Figs 3f and 4e). At E16.5, a Hic1–/– embryo exhibited a severe ventral body wall defect (organoschesis) with loops of intestine and the tip of the liver protruding out of the body cavity (Fig. 3e and g). Although a Hic1+/– littermate still had a small, presumably physiological, umbilical hernia at this stage, the defect seen in the Hic1–/– embryo was much larger and involved a larger area of the ventral body wall. Omphalocele has been observed in multiple MDS patients, and on this basis it has been proposed that one or more genes within the critical deletion region are involved in the return of the midgut from the body stalk and/or the closure of the ventral body wall (22).
No neuronal migration defect or disorganization of the cerebral cortex, similar to that reported for Lis1 graded reduction mice (20), was detected in any of the Hic1–/– term embryos without gross developmental defects. In all cases, a distinct intermediate zone was seen, which matched wild-type littermate controls (data not shown).
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DISCUSSION |
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The characteristics of the family of genes to which HIC1 belongs are quite consistent with a role for the gene in developmental processes. Members of the POZ domain family of zinc-finger transcription factors all possess a structure similar to that of HIC1, with a highly conserved N-terminal POZ domain and a variable number of Krüpple-type zinc fingers towards the C-terminus (27,28). In Drosophila, POZ domain family members are involved in repression of pair-rule segmentation genes (tramtrack) (29,30), chromatin decondensation and positive regulation of Bithorax complex expression (E(var)3–93D) (31), orchestration of metamorphosis (Broad-Complex) (32–35), axon growth and guidance (lola) (36) and morphogenesis of ovaries, antennae and legs (bric à brac) (37). Given this background, it is not surprising that we now find HIC1 to play a critical role in mammalian development.
HIC1 has been a candidate for involvement in MDS since its initial description, and recent studies by Grimm et al. (38) are consistent with this, showing that murine Hic1 is ubiquitously expressed and found in embryonic precursors to many structures affected in MDS patients. Here, in the initial analysis of the dramatic and obvious defects produced in Hic1–/– embryos, we have presented functional evidence that this gene is involved in the development of structures (Table 2) affected in some MDS patients. MDS patients are hemizygous for the deletion region, and although it is true that Hic1+/– mice did not show gross abnormalities, this finding is not inconsistent with a role for HIC1 in the disease. Except for the brain defect and associated mental retardation, many elements of the MDS are subtle, such as characteristic facial features and splaying of digits, and these features are either not readily identifiable in heterozygous mice, or they are absent, as is sometimes the case with mouse models of human disease (39,40). Highly detailed measurements will be necessary to determine whether subtle features of MDS are found in Hic1+/– mice.
Our observation that the cortical neuronal migration defect reported in mice with reduced Lis1 activity (20) could not be seen in Hic1-deficient term embryos is consistent with the hypothesis that reduction of Lis1 activity alone is responsible for the brain defects seen in MDS patients. Strong evidence from patients with isolated lissencephaly sequence and point mutations in Lis1 (17,18), combined with murine gene targeting experiments (19,20), showed that this is most likely the case. However, prior to this study, there have been no reports of mutations or gene targeting of other genes within the critical deletion region to confirm this.
In summary, our findings strengthen the candidacy of HIC1 as a gene involved in MDS by showing that its murine homolog is involved in the development of the head, face, limbs and ventral body wall, all of which can be abnormal in MDS patients.
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MATERIALS AND METHODS |
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Cloning and sequencing of Hic1 genomic clones
We isolated a 14 kb mouse Hic1 genomic clone from a 129/Sv/J phage library (Stratagene, La Jolla, CA). Three different human HIC1 probes were used to screen ~600 000 plaques, under previously described hybridization conditions (1). Phage inserts were subcloned into plasmid vectors using standard techniques (41). Automated sequencing of genomic clones was performed by the dye terminator method on ABI Prism sequencers (PE Biosystems, Foster City, CA) using manufacturer’s protocols.
Transcription/translation reactions
Rabbit reticuloctye lysates were programmed with genomic clones containing the human HIC1 gene according to manufacturer’s protocol (TnT kit; Promega, Madison, WI). Protein was sized by 6% sodium dodecyl sulfate–polyacrylamide gel electrophoresis.
RT–PCR
For confirmation of splicing patterns in adult mouse and human tissues, cDNA synthesis was performed according to Life Technologies’ Superscript II protocol (Life Technologies, Rockville, MD). Two microliters of each RT reaction was amplified in a 50 µl reaction containing 5 µl of 5x PCR buffer, 1.25 mM dNTPs, 300 ng of each primer and 1.25 U of Taq polymerase. Cycling conditions were: 95°C for 5 min, hold at 85°C and add Taq; 95°C for 30 s, 65°C for 30 s, 72°C for 45 s (30 cycles); 72°C for 4 min. The following primers were used: P173, 5'-CCC CTG GAT CCG CCG TCA GCC-3'; P174, 5'-TTC GCG CTC TGC CCG CCA C-3'; P175, 5'-ATG ATC ACG TCG CAC AAG AAG CC-3'. PCR products were cloned using Invitrogen’s Original TA Cloning kit (Invitrogen, Carlsbad, CA) and sequenced as described above.
For detection of Hic1 transcripts in mouse embryos, cDNA synthesis was performed exactly as described in Life Technologies’ Thermoscript protocol. Using primers which amplify a 546 bp region of Hic1 transcript beginning at zinc finger 2 (P177, 5'-CGT GCG ACA AGA GCT ACA AGG AC-3'; P106, 5'-GAG GCT CTC CAG CGC CAC CTT G-3'), PCR was performed as described in Life Technologies’ PCRx Enhancer/Platinum Taq protocol. As an internal control, Gapdh mRNA was amplified (307 bp product) with the following primers: hGAPDH1, 5'-CGG AGT CAA CGG ATT TGG TCG TAT-3'; mGAPDH2, 5'-GCC TTC TCC ATG GTG GTG AAG AC-3'.
Expression analysis
Commercial filters of poly(A) RNA from a variety of adult mouse tissues and whole mouse embryos (Clontech, Palo Alto, CA) were hybridized with radiolabeled probes as previously described (1). Filters were exposed on a Phosphorimager system (Molecular Dynamics, Sunnyvale, CA).
Generation of Hic1-deficient mice
The targeting construct was created by placing a 2.3 kb genomic fragment 3' to a selection cassette containing a splice acceptor site, a ß-galactosidase reporter gene and a phosphoglucokinase (PGK)-driven G418 resistance gene (42). A 2.6 kb genomic fragment containing all but 200 bp of sequence upstream of the ATG was cloned 5' to the selection cassette. Negative selection was provided by a thymidine kinase gene 3' to the downstream genomic fragment. (Details of cloning are available on request.) Plasmid DNA was prepared using the Plasmid Mega-Prep kit (Qiagen, Valencia, CA), and linearized with AhdI. J1 ES cells were grown, electroporated and double-selected with G418 (350 µg/ml; Sigma-Aldrich, St Louis, MO) and gancyclovir (2 µM; Syntex, Mississauga, Ontario, Canada) as previously described (43). Southern blot analysis with probes A and B (Fig. 1b) was used to isolate homologous recombinant clones, which were expanded for injection into day 3 C57BL/6 blastocysts. Pups highly chimeric for agouti coat color were selected for further breeding to C57BL/6 mates, and progeny receiving the 129/Sv genome were identified by the agouti coat color trait.
Genotyping of mice
Genotyping of tail, blood and embryo DNA was performed using two different dual-product PCR reactions, one at each end of the junction between the replaced region and endogenous Hic1 sequences. The 5' reaction primers are: P1, 5'-AAA CAG ATT TCT CCC TGG AAG-3'; P2, 5'-TCA AGG AAA CCC TGG ACT AC-3'; P3, 5'-ATG AGT AGC AAG CCT GGA TG-3'. Primers P4 (5'-CTC TCC AAC TGT GCC CAA TG-3'), P5 (5'-TTC CTT GAC CCT GGA AGG TG-3') and P6 (5'-GCA TCC ACT CTG GAG AGA AG-3') were used for the 3' reaction. Each 50 µl reaction contained 5 µl of 10x PCRx amplification buffer, 10 µl of 10x PCRx enhancer solution (Life Technologies), 0.2 mM dNTPs (Pharmacia, Piscataway, NJ), 1.5 mM MgSO4, 450 ng of P1 or P4, 150 ng of P2 or P5, 300 ng of P3 or P6, 2.5 U of Platinum Taq DNA polymerase (Life Technologies) and 100–200 ng of genomic DNA. The cycling conditions are: 98°C for 2 min; 51°C for 90 s, 72°C for 90 s, 98°C for 30 s (30 cycles); 51°C for 90 s, 72°C for 5 min. Products were electrophoresed on 1.5% agarose gels in 1x Tris–acetate EDTA buffer at 80 V for 50 min and photographed using an Eagle Eye digital camera system (Stratagene).
Histological analysis
Embryos were fixed in Bouin’s solution or in 1x phosphate-buffered saline plus 4% paraformaldehyde, 0.2% glutaraldehyde, photographed whole, embedded in paraffin and sectioned at a thickness of 5 µm. Serial sagittal sections were cut from the midline laterally, and every fourth section was mounted on a slide. Sections were stained with hematoxylin and eosin. Some embryos were stained for gross examination of ß-galactosidase activity (44), and 5 µm frozen sections were stained with hematoxylin and eosin for histological examination.
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ACKNOWLEDGEMENTS |
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The authors wish to thank Roger Reeves for the gift of the ploxPSABgalneo plasmid, and Ann Lawler for J1 ES cells. This work was supported by NIH grant no. CA43318.
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +1 410 955 8506; Fax: +1 410 614 9884; Email: sbaylin@welchlink.welch.jhu.edu
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