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PubMed1995

Identification of optimized target sequences for the GLI3 zinc finger protein.

GLI3 represents an important control gene for development and differentiation of several body structures. Reduction in gene dosage already leads to severe perturbation, especially of limb morphogenesis. The gene encodes a zinc finger protein that likely functions as a transcriptional modulator. Because the five zinc fingers should be capable of recognizing an extended stretch of genomic DNA, we sought to identify sequences bound by GLI3 that may facilitate the search for target genes acting downstream of GLI3. Starting from the nonamer DNA binding sequence of the highly related GLI protein, we employed an oligonucleotide selection protocol to determine an optimized binding sequence for the GLI3 protein. The resulting sequence bound by the GLI3 zinc fingers consists of 16 nucleotides and shows a high degree of similarity to sequences bound by the GLI and tra-1 proteins. Comparison with protein-DNA interactions in the known crystal structure of the GLI-DNA complex suggests relevant interactions of additional amino acids of GLI3 with its target site. The newly identified GLI3 target sequence should prove very useful for both the structural analysis of the protein-DNA complex and the search for genes whose expression is subject to regulation by the GLI3 gene product.

Base Sequence↗
PubMed1999

Gli3 is required for Emx gene expression during dorsal telencephalon development.

Dentate gyrus and hippocampus as centers for spatial learning, memory and emotional behaviour have been the focus of much interest in recent years. The molecular information on its development, however, has been relatively poor. To date, only Emx genes were known to be required for dorsal telencephalon development. Here, we report on forebrain development in the extra toes (Xt(J)) mouse mutant which carries a null mutation of the Gli3 gene. This defect leads to a failure to establish the dorsal di-telencephalic junction and finally results in a severe size reduction of the neocortex. In addition, Xt(J)/Xt(J) mice show absence of the hippocampus (Ammon's horn plus dentate gyrus) and the choroid plexus in the lateral ventricle. The medial wall of the telencephalon, which gives rise to these structures, fails to invaginate during embryonic development. On a molecular level, disruption of dorsal telencephalon development in Xt(J)/Xt(J) embryos correlates with a loss of Emx1 and Emx2 expression. Furthermore, the expression of Fgf8 and Bmp4 in the dorsal midline of the telencephalon is altered. However, expression of Shh, which is negatively regulated by Gli3 in the spinal cord, is not affected in the Xt(J)/Xt(J) forebrain. This study therefore implicates Gli3 as a key regulator for the development of the dorsal telencephalon and implies Gli3 to be upstream of Emx genes in a genetic cascade controlling dorsal telencephalic development.

Animals↗
PubMed1999

Point mutations throughout the GLI3 gene cause Greig cephalopolysyndactyly syndrome.

Greig cephalopolysyndactyly syndrome, characterized by craniofacial and limb anomalies (GCPS; MIM 175700), previously has been demonstrated to be associated with translocations as well as point mutations affecting one allele of the zinc finger gene GLI3. In addition to GCPS, Pallister-Hall syndrome (PHS; MIM 146510) and post-axial polydactyly type A (PAP-A; MIM 174200), two other disorders of human development, are caused by GLI3 mutations. In order to gain more insight into the mutational spectrum associated with a single phenotype, we report here the extension of the GLI3 mutation analysis to 24 new GCPS cases. We report the identification of 15 novel mutations present in one of the patient's GLI3 alleles. The mutations map throughout the coding gene regions. The majority are truncating mutations (nine of 15) that engender prematurely terminated protein products mostly but not exclusively N-terminally to or within the central region encoding the DNA-binding domain. Two missense and two splicing mutations mapping within the zinc finger motifs presumably also interfere with DNA binding. The five mutations identified within the protein regions C-terminal to the zinc fingers putatively affect additional functional properties of GLI3. In cell transfection experiments using fusions of the DNA-binding domain of yeast GAL4 to different segments of GLI3, transactivating capacity was assigned to two adjacent independent domains (TA(1)and TA(2)) in the C-terminal third of GLI3. Since these are the only functional domains affected by three C-terminally truncating mutations, we postulate that GCPS may be due either to haploinsufficiency resulting from the complete loss of one gene copy or to functional haploinsufficiency related to compromised properties of this transcription factor such as DNA binding and transactivation.

Animals↗
PubMed1996

Transcription factors in disease.

Mutations affecting several predominantly tissue-specific transcriptional regulators have recently been associated with disease phenotypes. Although the mutational spectrum is variable, many of the reported cases involve clear loss-of-function mutations-such as Waardenburg syndrome type 1, aniridia and Rubinstein-Taybi syndrome-suggesting that the genetic mechanism involved in disease is haplo-insufficiency. The high degree of dosage sensitivity often appears to affect only a subset of the tissues that express the gene. Position effects with cytogenetic rearrangements well outside the coding region have been implicated for four of the genes discussed: POU3F4, SOX9, PAX6, and GL13.

Animals↗
PubMed1993

Gli3 expression is affected in the morphogenetic mouse mutants add and Xt.

We investigated the relation between the recessive mutation add caused by insertional mutagenesis of a transgene and the dominant mutation extra-toes (Xt) which display similar effects on limb morphogenesis. The transgene insertion in add mapped close to the 5' end of the zinc finger gene Gli3 and 5'sequences of Gli3 were deleted in Xt. Expression analysis revealed a reduction of the Gli3 RNA level in both add and Xt mice. Thus, it is very likely that add and Xt are alleles of the Gli3 gene.

Alleles↗
PubMed2005

Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations.

Mutations in the GLI3 zinc-finger transcription factor gene cause Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS), which are variable but distinct clinical entities. We hypothesized that GLI3 mutations that predict a truncated functional repressor protein cause PHS and that functional haploinsufficiency of GLI3 causes GCPS. To test these hypotheses, we screened patients with PHS and GCPS for GLI3 mutations. The patient group consisted of 135 individuals: 89 patients with GCPS and 46 patients with PHS. We detected 47 pathological mutations (among 60 probands); when these were combined with previously published mutations, two genotype-phenotype correlations were evident. First, GCPS was caused by many types of alterations, including translocations, large deletions, exonic deletions and duplications, small in-frame deletions, and missense, frameshift/nonsense, and splicing mutations. In contrast, PHS was caused only by frameshift/nonsense and splicing mutations. Second, among the frameshift/nonsense mutations, there was a clear genotype-phenotype correlation. Mutations in the first third of the gene (from open reading frame [ORF] nucleotides [nt] 1-1997) caused GCPS, and mutations in the second third of the gene (from ORF nt 1998-3481) caused primarily PHS. Surprisingly, there were 12 mutations in patients with GCPS in the 3' third of the gene (after ORF nt 3481), and no patients with PHS had mutations in this region. These results demonstrate a robust correlation of genotype and phenotype for GLI3 mutations and strongly support the hypothesis that these two allelic disorders have distinct modes of pathogenesis.

Abnormalities, Multiple↗
PubMed1991

GLI3 zinc-finger gene interrupted by translocations in Greig syndrome families.

The Greig cephalopolysyndactyly syndrome (GCPS) is an autosomal dominant disorder affecting limb and craniofacial development in humans. GCPS-affected individuals are characterized by postaxial polysyndactyly of hands, preaxial polysyndactyly of feet, macroephaly, a broad base of the nose with mild hypertelorism and a prominent forehead. The genetic locus has been pinpointed to chromosome 7p13 by three balanced translocations associated with GCPS in different families. This assignment is corroborated by the detection of two sporadic GCPS cases carrying overlapping deletions in 7p13 (ref. 7), as well as by tight linkage of GCPS to the epidermal growth factor receptor gene in 7p12-13 (ref. 8). Of the genes that map to this region, those encoding T cell receptor-gamma, interferon-beta 2, epidermal growth factor receptor, and Hox1.4, a potential candidate gene for GCPS, have been excluded from the region in which the deletions overlap. Here we show that two of the three translocations interup the GLI3 gene, a zinc-finger gene of the GLI-Krüppel family already localized to 7p13 (refs 5, 6). The breakpoints are within the first third of the coding sequence. In the third translocation, chromosome 7 is broken at about 10 kilobases downstream of the 3' end of GLI3. Our results indicate that mutations disturbing normal GLI3 expression may have a causative role in GCPS.

Chromosome Deletion↗
PubMed1997

GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome.

Pallister-Hall syndrome (PHS, M146510) was first described in 1980 in six newborns. It is a pleiotropic disorder of human development that comprises hypothalamic hamartoma, central polydactyly, and other malformations. This disorder is inherited as an autosomal dominant trait and has been mapped to 7p13 (S. Kang et al. Autosomal dominant Pallister-Hall syndrome maps to 7p13. Am. J. Hum. Genet. 59, A81 (1996)), co-localizing the PHS locus and the GLI3 zinc finger transcription factor gene. Large deletions or translocations resulting in haploinsufficiency of the GLI3 gene have been associated with Greig cephalopolysyndactyly syndrome (GCPS; M175700) although no mutations have been identified in GCPS patients with normal karyotypes. Both PHS and GCPS have polysyndactyly, abnormal craniofacial features and are inherited in an autosomal dominant pattern, but they are clinically distinct. The polydactyly of GCPS is commonly preaxial and that of PHS is typically central or postaxial. No reported cases of GCPS have hypothalamic hamartoma and PHS does not cause hypertelorism or broadening of the nasal root or forehead. The co-localization of the loci for PHS and GCPS led us to investigate GLI3 as a candidate gene for PHS. Herein we report two PHS families with frameshift mutations in GLI3 that are 3' of the zinc finger-encoding domains, including one family with a de novo mutation. These data implicate mutations in GLI3 as the cause of autosomal dominant PHS, and suggest that frameshift mutations of the GLI3 transcription factor gene can alter the development of multiple organ systems in vertebrates.

Abnormalities, Multiple↗
PubMed1994

Isolation of a yeast artificial chromosome contig spanning the Greig cephalopolysyndactyly syndrome (GCPS) gene region.

Disruption of the zinc finger gene GLI3 has been shown to be the cause of Greig cephalopolysyndactyly syndrome (GCPS), at least in some GCPS translocation patients. To characterize this genomic region on human chromosome 7p13, we have isolated a YAC contig of more than 1000 kb including the GLI3 gene. In this contig the gene itself spans at least 200-250 kb. A CpG island is located in the vicinity of the 5' region of the known GLI3 cDNA, implying a potential promoter region.

Abnormalities, Multiple↗
PubMed2001

Anorectal malformations caused by defects in sonic hedgehog signaling.

Anorectal malformations are a common clinical problem affecting the development of the distal hindgut in infants. The spectrum of anorectal malformations ranges from the mildly stenotic anus to imperforate anus with a fistula between the urinary and intestinal tracts to the most severe form, persistent cloaca. The etiology, embryology, and pathogenesis of anorectal malformations are poorly understood and controversial. Sonic hedgehog (Shh) is an endoderm-derived signaling molecule that induces mesodermal gene expression in the chick hindgut. However, the role of Shh signaling in mammalian hindgut development is unknown. Here, we show that mutant mice with various defects in the Shh signaling pathway exhibit a spectrum of distal hindgut defects mimicking human anorectal malformations. Shh null-mutant mice display persistent cloaca. Mutant mice lacking Gli2 or Gli3, two zinc finger transcription factors involved in Shh signaling, respectively, exhibit imperforate anus with recto-urethral fistula and anal stenosis. Furthermore, persistent cloaca is also observed in Gli2(-/-);Gli3(+/-), Gli2(+/-);Gli3(-/-), and Gli2(-/-);Gli3(-/-) mice demonstrating a gene dose-dependent effect. Therefore, Shh signaling is essential for normal development of the distal hindgut in mice and mutations affecting Shh signaling produce a spectrum of anorectal malformations that may reveal new insights into their human disease equivalents.

Anal Canal↗
PubMed1997

Gene structure and allelic expression assay of the human GLI3 gene.

The GLI3 gene encodes a putative zinc finger transcription factor that is important in early vertebrate development. Haploinsufficiency of this gene has been associated with the Greig cephalopolysyndactyly syndrome and truncation mutations cause Pallister-Hall syndrome. In the course of studies to determine the etiology of Pallister-Hall syndrome, we required knowledge of the fine structure of GLI3 to perform detailed genetic and physical mapping and mutation screening of this gene. The coding region of GLI3 is composed of 14 exons, including a large exon of more than 2500 bp. In addition, the gene contains two intragenic dinucleotide repeats, and four single-base pair polymorphisms in the coding region. We have used these coding region polymorphisms to design an allele-specific expression study that will be useful for studying patients with Greig cephalopolysyndactyly syndrome. In addition, GLI3 should be considered a candidate gene for related developmental anomalies of humans. Such hypotheses will be more readily addressed with the availability of the fine structure of the gene and the allele-expression assay.

Abnormalities, Multiple↗
PubMed1997

Cloning and sequencing of the mouse Gli2 gene: localization to the Dominant hemimelia critical region.

The GLI family of zinc finger genes has been implicated in both neoplastic and developmental disorders. We have cloned and sequenced the mouse homolog of the zinc finger gene Gli2 and demonstrated significant similarity to the human GLI3 gene. We have also localized Gli2 to mouse chromosome 1, in the vicinity of the morphogenetic mutation Dominant hemimelia (Dh), which is characterized by tibial hemimelia, poly/oligodactyly, and a number of visceral abnormalities, most strikingly absence of the spleen. Using a Gli2-associated microsatellite, we demonstrated no recombination between Dh and Gli2 in a Dh intraspecific backcross. Gli2 is expressed in Dh heterozygotes and homozygotes. However, using a combination of mismatch analysis and direct sequencing, we have failed to identify any mutations in the coding sequence of Gli2 from Dh. We have also demonstrated that it is unlikely that there are any Gli genes in the mouse genome in addition to the previously described Gli, Gli2, and Gli3.

Amino Acid Sequence↗
PubMed1997

Evidence for the involvement of the Gli gene family in embryonic mouse lung development.

Murine Gli, Gli2, and Gli3 are zinc finger genes related to Drosophila cubitus interuptus, a component of the hedgehog signal transduction pathway. In the embryonic lung, all three Gli genes are strongly expressed at the pseudoglandular stage, in distinct but overlapping domains of the mesoderm. Expression of Gli and Gli3, but not of Gli2, is subsequently downregulated at the canalicular stage, coincident with a decline in the expression of sonic hedgehog (Shh) and the hedgehog receptor gene, patched (Ptc). Overexpression of Shh in the lung results in increased levels of Ptc mRNA. Gli, but not Gli2, is also upregulated, suggesting a differential involvement of the Gli genes in the regulation of Ptc by SHH during lung development. Gli3 is not upregulated by Shh overexpression. However, its importance for lung development is shown by the finding that Gli3XtJ embryos, homozygous for a mutation involving a deletion of the Gli3 gene, have a stereotypic pattern of abnormalities in lung morphogenesis. The pulmonary defects in these embryos, consisting of localized shape changes and size reductions, correlate with normal Gli3 expression. Thus, our data indicate that one of the Gli genes, Gli3, is essential for normal lung development, and that another, Gli, can be placed downstream of Shh signaling in the lung.

Animals↗
PubMed2000

Shh and Wnt signaling pathways converge to control Gli gene activation in avian somites.

The regulation of the Gli genes during somite formation has been investigated in quail embryos. The Gli genes are a family encoding three related zinc finger transcription factors, Gli1, Gli2 and Gli3, which are effectors of Shh signaling in responding cells. A quail Gli3 cDNA has been cloned and its expression compared with Gli1 and Gli2. These studies show that Gli1, Gli2 and Gli3 are co-activated at the time of somite formation, thus providing a mechanism for regulating the initiation of Shh signaling in somites. Embryo surgery and paraxial mesoderm explant experiments show that each of the Gli genes is regulated by distinct signaling mechanisms. Gli1 is activated in response to Shh produced by the notochord, which also controls the dorsalization of Gli2 and Gli3 following their activation by Wnt signaling from the surface ectoderm and neural tube. This surface ectoderm/neural tube Wnt signaling has both negative and positive functions in Gli2 and Gli3 regulation: these signals repress Gli3 in segmental plate mesoderm prior to somite formation and then promote somite formation and the somite-specific activation of Gli2 and Gli3. These studies, therefore, establish a role for Wnt signaling in the control of Shh signal transduction through the regulation of Gli2 and Gli3, and provide a mechanistic basis for the known synergistic actions of surface ectoderm/neural tube and notochord signaling in somite cell specification.

Amino Acid Sequence↗
PubMed1999

The mouse mutation Pdn (Polydactyly Nagoya) is caused by the integration of a retrotransposon into the Gli3 gene.

Mutations in the Gli3 gene are associated with a preaxial polydactyly in several mouse mutants such as extra-toes (Xt). The semidominant mouse mutant Pdn (Polydactyly Nagoya) is characterized by a mild polydactyly on the anterior side of the hind limbs. Homozygous Pdn mice show a more severe polydactyly, additional skeletal malformations, and abnormal brain development. Herein, we report the molecular basis of Pdn, being the integration of an Early Transposon (ETn) into the Gli3 gene. As a consequence, several novel Gli3 mRNAs are generated by alternatively spliced transcripts.

Amino Acid Sequence↗