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ZINC FINGER TRANSCRIPTION FACTORS IN SKELETAL DEVELOPMENT

CIHR Group in Matrix Dymanics, Faculty of Dentistry, University of Toronto, 239-150 College Street, Toronto, ON M5S 3E2, Canada;

Correspondence: ^* corresponding author, b.ganss{at}utoronto.ca

Abstract

(1) Introduction

SKELETAL MORPHOGENESIS

(a) Patterning/migration

(b) Mesenchymal differentiation

(c) Organogenesis

MOLECULAR REGULATION OF MINERALIZED TISSUE FORMATION

TRANSCRIPTIONAL REGULATION

(2) Zinc Finger Transcription Factors

C2H2 ZINC FINGER PROTEINS

KRAB/C2H2 ZINC FINGER PROTEINS

(3) Zinc Finger Genes in Skeletal Development

(3.1) KRAB-ZINC FINGER PROTEINS

AJ18

Zfp60

NT2

Znf8

(3.2) KRüPPEL-RELATED GENES

c-Krox

Krox-20

Krox-24

Krox-26

Sp family

Sp3

Sp7 (Osterix)

Gli family

TIEG family

(3.3) OTHER ZINC FINGER FACTORS

Schnurri

CRYBP1

CIZ

YY1

OAZ

A Concluding Note

The Future

REFERENCES

	Abstract

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Key Words: Zinc finger • transcription • bone • cartilage • teeth

	(1) Introduction

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SKELETAL MORPHOGENESIS
The skeletal elements (teeth, bones, cartilage, and connective tissue) provide mechanical support, protection of vital organs, mineral homeostasis for calcium and phosphate ions and are the source of hematopoietic cells. Formation of the skeleton occurs by either intramembranous ossification, whereby mesenchyme-derived cells directly differentiate into osteoblasts, or by endochondral ossification, characterized by the existence of a cartilage intermediate that is later replaced by bone. Once the adult skeleton is formed, homeostasis in mineralized tissues is maintained by the balanced action of bone-forming osteoblasts and bone-resorbing osteoclasts (Parfitt, 1994). In humans, this balance between bone formation and resorption shifts later in life toward a net bone loss, leading to pathological conditions such as osteoporosis. Skeletal tissues that are lost—not only to age-related degeneration or destruction but also to trauma or the removal of cancerous tissue (e.g., osteosarcoma)—are not at all or only incompletely regenerated without intervention.

The formation of the skeleton occurs in three stages:

(a) Patterning/migration
From an ontogenetic perspective, mineralized tissues in vertebrates are derived from three distinct embryonic lineages: The axial skeleton is derived from paraxial mesoderm (somites), the appendicular skeleton originates from lateral plate mesodermal cells, and the craniofacial skeleton is a derivative of cranial neural crest cells. Neural-crest-derived cells migrate to sites of craniofacial skeleton formation, where they differentiate directly or under the influence of epithelial-mesenchymal interactions. Mesoderm-derived cells migrate to regions of future axial and appendicular skeletal development, where they form mesenchymal cell condensations.

(b) Mesenchymal differentiation
Condensations of skeletal mesenchymal cells differentiate into chondrocytes to form a model framework of cartilage (Hall and Miyake, 2000) that is subsequently replaced by bone (endochondral ossification). Cells of the future craniofacial skeleton and parts of the clavicle migrate and differentiate directly into bone cells without forming a cartilage intermediate (intramembranous ossification). The formation of teeth as mineralized organs is dependent on iterative and reciprocal interactions between epithelial and neural-crest-derived mesenchymal cells, resulting in the differentiation of epithelium-derived, enamel-forming ameloblasts and mesenchyme-derived, dentin-forming odontoblasts (Peters and Balling, 1999).

(c) Organogenesis
Cells in mesenchymal condensations of future long bones express cartilage-specific genes and produce a chondrocyte-specific extracellular matrix. The cells in the center of these condensations hypertrophy, undergo apoptosis, and allow for the invasion of blood vessels and replacement by osteoblasts. Further growth is then achieved by the controlled and directional differentiation of chondrocytes from proliferating to hypertrophic cells, thus determining the future shape and size of adult long bones. Cells of the craniofacial skeleton synthesize an osteoid matrix, which mineralizes under the guidance of non-collagenous extracellular matrix proteins such as bone sialoprotein (BSP) (reviewed by Ganss et al., 1999), ultimately to form the mature skeleton. For a detailed review on skeletogenesis, see Karsenty (1998).

MOLECULAR REGULATION OF MINERALIZED TISSUE FORMATION
Skeletal development is controlled by systemic hormones and local paracrine and autocrine factors. While the molecular mechanisms of growth regulation by systemic factors are still largely unknown, it is evident that the locally restricted, molecular regulation of skeletal growth is achieved by the activation of signaling cascades via secreted molecules and the modulation of gene expression in the target cell through responsive transcription factors. The most prominent of these signaling cascades involve members of the Fibroblast Growth Factor (FGF) and Bone Morphogenetic Protein (BMP) families as well as Parathyroid-hormone-related peptide (PTHrP) and the hedgehog family member Indian hedgehog (Ihh).

Osteoblasts and chondrocytes, which form bone and cartilage, respectively, are primarily derived from mesenchymal stem cells, which also have the ability to form fat and muscle through the differentiation pathways of adipocytes and myoblasts, respectively (Grigoriadis et al., 1988; Caplan and Bruder, 2001). Studies of mesenchymal stem cell differentiation have revealed the existence of ‘master genes’ that are essential for normal development. Interestingly, all of these master regulators of early mesenchymal cell differentiation code for transcription factors. However, unlike the differentiation pathways of adipocytes (Rosen and Spiegelman, 2000), myoblasts (Perry and Rudnicki, 2000), or even the macrophage-derived osteoclasts (Boyle et al., 2003), which have been defined in some detail, the molecular mechanisms of bone cell differentiation are only beginning to be unraveled.

The paucity of molecules implicated during skeletal differentiation has led to an enormous effort by our and other labs to identify the transcription factors involved in skeletal cell differentiation. The elucidation of the underlying molecular mechanisms has been enormously assisted by the cloning of BMPs, the identification of their serine/threonine kinase types I and II receptors, and the downstream signaling proteins such as Smads (for reviews, refer to Miyazono, 1999; Canalis et al., 2003). Great advances have been made recently with the identification and characterization of Runx2/Cbfa1/Osf2 (Ducy et al., 1997; Komori et al., 1997; Mundlos et al., 1997; Otto et al., 1997), and Osterix (Osx; Nakashima et al., 2002): two putative transcription factors and BMP targets whose null phenotypes result in the complete absence of bone in mutant mice.

However, among the additional proteins that have recently been identified as playing a role in skeletal differentiation, an emerging family of transcription factors appears to be prominent: the C2H2 zinc-finger-containing gene family, which includes Osx. This is not an unexpected finding, given that the C2H2 zinc finger is the most common motif present in putative transcription factors (Tupler et al., 2001). Considering the recent surge of C2H2 zinc finger genes identified to be involved in skeletal development, we believe that this prominent family of proteins and their proposed functions during skeletal differentiation must be highlighted.

TRANSCRIPTIONAL REGULATION
Gene expression, which is the basis for most biological processes, including skeletogenesis, can be defined as the production of a functional biomolecule (generally a protein) from the information that is coded by genomic DNA. According to the central dogma of molecular biology, the first step in gene expression is the production of an RNA molecule from a DNA template during transcription. This RNA intermediate can be edited in multiple ways and serves as a template for subsequent protein synthesis or translation. Transcription is likely to be the most intricately regulated process during gene expression, and the underlying molecular mechanisms have been studied in much detail since the discovery, in 1960, of RNA polymerase II (RNAP II) as the active RNA-synthesizing enzyme.

It is now well-established that RNA polymerase II cannot initiate transcription alone and instead requires myriad basal transcription factors and associated factors (Smale and Kadonaga, 2003). Thus, the term ‘transcriptosome’ has been coined to reflect the heterogeneous nature of this multimeric assembly. The transcription initiation complex appears to be a common requirement for the initiation and maintenance of basal transcription for protein-encoding eukaryotic genes within the chromatin environment. Many excellent review articles have been published that describe the composition of the pre-initiation complex and the mechanisms that govern transcriptional initiation and elongation (Reese, 2003; Shilatifard et al., 2003).

Beyond these basal transcription mechanisms, the regulation of gene transcription is governed by proteins known as transcription factors (Fig. 1). Transcription factors are involved in virtually all fundamental biological processes, such as patterning, development, differentiation, cell proliferation, and the cellular response to external stimuli. They generally consist of at least two functionally distinct domains: a DNA-binding domain (DBD) that recognizes and binds to specific DNA sequence elements in the promoter of target genes; and a protein-interacting transactivation domain (TAD) that influences the rate of transcription by interacting with components of the basal transcription complex or other transcription factors.

View larger version (17K): [in this window] [in a new window]   Figure 1. A simplistic view of regulatory mechanisms of gene transcription. The RNA-transcribing enzyme, RNA polymerase II (red), requires general transcription factors (TFII) D, A, B, F, E, and H (blue), which themselves consist of multiple subunits, to recognize the transcription start site via the TATA box or related sequences in the core promoter. The sum of these factors, known as the pre-initiation complex (PIC), is required for basal transcription. Transcription factors (green) bind to specific DNA sequences (red) via their DNA-binding domain (DBD) and modulate the rate of transcription via their transactivation domain(s) (TAD).

The largest transcription factor family contains a DNA-binding motif known as the zinc finger. Based on the structure and spatial arrangement of this domain, the zinc finger gene family can be further subdivided into several classes, and many attempts have been made to categorize them. Several members of the zinc-finger-containing steroid hormone receptor family, such as the vitamin D or retinoic acid receptors, have been long known to play important roles in bone metabolism and skeletal development.

In this review, we focus on proteins that contain so-called C2H2 zinc fingers, in which the zinc-binding motif is determined by the presence of two cysteine and two histidine residues that engage in a four-coordinate bond with a single zinc ion. One of the few well-defined transactivation domains, the Krüppel-associated box (KRAB) domain, occurs in approximately one-third of all C2H2 proteins and mediates transcriptional repression (see below).

	(2) Zinc Finger Transcription Factors

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C2H2 ZINC FINGER PROTEINS
The zinc finger proteins are characterized by their utilization of zinc ions as structural components. A structural role for zinc was first proposed in Xenopus TFIIIA (Hanas et al., 1983), and subsequently the C2H2 zinc finger motif was revealed (Miller et al., 1985). There are more than 10 different classes of zinc-binding motifs that have been identified and partially characterized, such as C₄ and C₂HC motifs, but the C₂H₂ (also known as TFIIIA/Krüppel) zinc finger motif is the most abundant DNA-binding motif among putative eukaryotic transcription factors (Tupler et al., 2001) (Fig. 2). The C2H2 motif, which is generally present in tandem arrays, consists of the sequence Y/F-X-C-X_2–4-C-X₃-F-X₅-L-X₂-H-X_3–5-H, where X represents variable amino acid residues. The structure of each zinc finger motif consists of two antiparallel β-strands followed by an -helix (Pavletich and Pabo, 1993). The two conserved cysteine and histidine side-chains (C2H2) form coordinate bonds with the zinc ion and, along with the three other conserved residues within the motif that pack to form a hydrophobic core, stabilize the structure (Figs. 3a, 3c). In addition to the conserved sequence within the zinc finger region, these proteins also share a highly conserved seven-amino-acid inter-finger spacer, TGEKP(Y/F)X. This sequence, commonly referred to as a H/C link, has recently been shown to be phosphorylated on its threonine residue during the mitotic stage of the cell cycle, thus inactivating the function of the protein (Dovat et al., 2002). The authors suggest that the phosphorylation of this linker may provide a global mechanism for inactivation of the C2H2 family.

View larger version (58K): [in this window] [in a new window]   Figure 2. Genome-wide comparison of transcription factor families in eukaryotes. The relative sizes of the transcription factor families, categorized according to their DNA-binding domain, among Homo sapiens, Drosophila melanogaster, Caenorhabditis elegans, and Saccharomyces cerevisiae are indicated. Data are derived from an analysis of eukaryotic proteomes according to the INTERPRO database, which incorporates Pfam, PRINTS, and Prosite. The transcription factor families shown are the largest in their category out of the 1502 protein families listed by Integrated ProteomicsTM Inc. (IPI). Reproduced with permission from Tupler et al.(2001).

View larger version (39K): [in this window] [in a new window]   Figure 3. C2H2 zinc finger motif. (A) The C2H2 zinc finger motif (2 Cys and 2 His residues bonded tetrahedrally to a Zn ion) consists of a short antiparallel β-sheet formed by two β-strands and hairpin turn, followed by an -helix (adapted from Lee et al., 1989). (B) Co-crystal structure of Zif268/DNA as determined by Pavletich and Pabo (1993). Note the -helices wrapped around the major groove of the DNA. N denotes the N-terminus. (C) β-strands (arrows) and hairpin turn (curved line), followed by an -helix (blue helix) that usually fits into the major groove of the target DNA. Conserved amino acids are underlined. Amino acids (red) at positions –1, +3, and +6 relative to the beginning of the -helix are primarily responsible for interactions with DNA.

The difficulties in our understanding of the rules governing ZFP interaction with duplex DNA are exacerbated by the fact that, although zinc finger proteins control a variety of fundamental biological events, the individual physiological roles of most C2H2 proteins are not well-understood. The broad expression of many ZFPs in mammalian tissues originally suggested that they are undiscerning proteins that sustain the expression of a multitude of basic maintenance genes. However, recent descriptions of mice that lack certain zinc finger transcription factors, and as a result show severe and often highly specific phenotypes, have completely changed this picture. In addition to interactions with DNA duplexes, C2H2 motifs have been shown to bind to RNA, DNA-RNA hybrids, and even macromolecules other than nucleic acids (reviewed by Berg and Shi, 1996). Recently, the C2H2 motif, and specifically the 11 residues concentrated within the -helical regions typically involved in nucleotide recognition, has been shown to be involved in specific protein dimerization (McCarty et al., 2003).

The C2H2 proteins can be divided superficially into two classes (although many alternative classifications have been proposed) according to the number of zinc finger motifs present within the protein sequence (Pieler and Bellefroid, 1994). In one class are the C2H2 genes that encode proteins such as Egr1 and the Sp family, which have fewer than 5 C2H2 motifs. The proteins in the group have generally been identified as transcriptional activators or repressors involved in the regulation of cell proliferation and differentiation. The proteins expressed by the second class of zinc finger genes have 5 or more zinc finger motifs. Apart from TFIIIA, which binds to both the 5S RNA gene and to 5S RNA (Theunissen et al., 1992), and MZF1, which regulates the CD34 gene (Morris et al., 1995), the physiological function(s) of the proteins in this class are largely unknown. This second class may further be broadly split into the proteins without and those with ‘KRAB’ domains. The KRAB/C2H2 genes are discussed in detail below.

KRAB/C2H2 ZINC FINGER PROTEINS
The KRAB domain is present in approximately one-third of all C2H2 proteins (Bellefroid et al., 1991), making this family one of the most widely distributed transcriptional repression domains yet identified in mammals (Margolin et al., 1994; Witzgall et al., 1994). KRAB domains are not found in prokaryotes, fungi, plants, or insects, but appear to have evolved with vertebrate organisms as a transcriptional repressor motif (Looman et al., 2002). When fused to a heterologous DNA-binding motif, the ~ 75 amino acid residues that comprise the KRAB domain repress both basal and activated transcription in transfected cells in a dose-dependent manner, and over large distances in the DNA sequence (Pengue et al., 1994; Deuschle et al., 1995; Moosmann et al., 1997). The KRAB domains can be separated into 3 subfamilies based on nucleic acid sequence alignment (Mark et al., 1999): subfamilies containing a KRAB A box alone, both A and B boxes, or an A box with a divergent B box. Notably, the A domain alone is sufficient for repressor activity, whereas the B domain has a lesser contribution (Margolin et al., 1994; Pengue et al., 1994). Insights into the molecular mechanism underlying this silencing activity came from the identification of a nuclear protein, TIF1β, also named KAP-1 (Friedman et al., 1996) or KRIP-1 (Kim et al., 1996). The KRAB domain associates with TIF1β (Kim et al., 1996; Le Douarin et al., 1996; Moosmann et al., 1996), which serves as a universal co-repressor for KRAB-containing transcription factors involved in silencing RNAP II- and III-, but not RNAP I-, dependent transcription (Moosmann et al., 1997). Based on sequence analysis, TIF1β was also identified as a member of the transcriptional intermediary factor 1 (TIF1) family (Le Douarin et al., 1996). In addition to TIF1β, the family includes TIF1, a putative nuclear receptor co-factor (Le Douarin et al., 1998; Zhong et al., 1999), and TIF1, whose function is unknown (Venturini et al., 1999). These three proteins are defined by the presence of three conserved regions: an amino-terminal RBCC (RING finger, B boxes, coiled coil) motif, which may be involved in intermolecular interactions that influence the targeting of subnuclear structures (Saurin et al., 1996); a PHD finger motif; and a bromodomain. The latter two motifs are often associated and are present in several transcriptional co-factors acting at the chromatin level (Aasland et al., 1995; Jeanmougin et al., 1997). The bromodomain has been shown to interact with lysine-acetylated peptides derived from histones H3 and H4, suggesting a chromatin-targeting function for this highly conserved domain (Dhalluin et al., 1999; Winston and Allis, 1999). Supporting the hypothesis that TIF1β may exert its co-repressor function by a chromatin-mediated mechanism, TIF1β is known to associate with and phosphorylate members of the heterochromatin protein 1 (HP1) family, a class of non-histone proteins with a well-established function in heterochromatin-mediated silencing in Drosophila (Nielsen et al., 1999; Schultz et al., 2001). Thus, TIF1β may mediate the repression function of the KRAB domain by HP1 interaction and histone deacetylation to induce formation of heterochromatin (Ryan et al., 1999; Lechner et al., 2000; Matsuda et al., 2001), thereby regulating chromatin dynamics.

Although KRAB/C2H2 proteins constitute two well-characterized motifs and make up one of the largest protein families, the function of these proteins in vivo is still unclear. KRAB domains are exclusively associated with C2H2 zinc finger proteins and with those proteins containing more than five C2H2 zinc finger motifs. Such proteins are most likely sequence-specific transcription repressors based on recent results (Zheng et al., 2000). However, the numerous C2H2 zinc finger motifs, along with the variable linker region joining the KRAB domain and C2H2 zinc fingers, suggest additional roles. Furthermore, very little is known regarding their genomic organization, and, to date, the promoter of only one KRAB/C2H2 gene has been characterized (Jheon et al., 2003).

	(3) Zinc Finger Genes in Skeletal Development

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Zinc finger proteins control a variety of fundamental cellular activities, and, more recently, several members of this transcription factor family have been identified as more specific regulators of skeletal development and mineralized tissue formation. Below, we attempt to review the most prominent members.

(3.1) KRAB-ZINC FINGER PROTEINS
Since approximately one-third of all C2H2 zinc finger genes contain an N-terminal KRAB domain, it is therefore not surprising that several of the newly identified zinc finger genes in skeletal tissues belong to this category. The presence of a KRAB domain allows us to speculate on the functions of these factors as transcriptional repressors.

AJ18
In response to osteo-inductive signals generated by the bone morphogenetic proteins (BMPs), undifferentiated mesenchymal stem cells can differentiate into bone-forming osteoblasts. A gene provisionally named AJ18, identified by differential display PCR, was up-regulated during osteoblast differentiation in fetal rat calvarial cells (FRCCs) treated with BMP-7 (Jheon et al., 1998). AJ18 encodes a novel 64-kDa protein comprised of a KRAB domain and 11 successive C2H2 zinc finger motifs and is believed to be a transcriptional repressor based on its sequence analysis. In support of this, AJ18 is localized in the nucleus, with intense staining within nuclear substructures that appear to be nucleoli or RNA processing sites; furthermore, a consensus DNA-binding site with the sequence 5'-CCACA-3' was revealed by a modified target detection assay (Jheon et al., 2001). The identified consensus sequence is surprisingly similar to the binding site for Runx2 (OSE2, osteoblast-specific element 2; 5'-ACCACA-3' [Ducy et al., 1997]). Subsequently, the over-expression of AJ18 (full-length and KRAB-less) was determined to abrogate the transactivation activity of Runx2 in a dose-dependent manner. Thus, it appears that AJ18 has the ability to compete with Runx2 for the OSE2. The competitive inhibitory function of AJ18 was supported by the decrease in BMP-7-induced alkaline phosphatase activity when AJ18 is over-expressed in C3H10T1/2 cells (Jheon et al., 2001), and by the observation (unpublished) that bone nodule formation is markedly reduced when AJ18 is over-expressed under the control of the bone-specific Col1a1 promoter (Rossert et al., 1996) in a rat bone marrow cell line. However, constitutive over-expression of exogenous AJ18 under the CMV promoter significantly enhances bone mineralization in this culture system (unpublished), indicating that AJ18 has opposing effects at different stages of osteodifferentiation.

To study the regulation of AJ18 gene expression, Jheon and co-workers (2003) screened a rat genomic library to obtain the 5'-flanking region of AJ18. Mapping of the transcription start site showed that the AJ18 gene contains an unusually long 2.3-kb 5'-untranslated region (5'-UTR) with the potential for strong secondary structure. Although sequence analysis of the immediate promoter region (–77 to +177) did not reveal TATA or CCAAT box motifs, transient transfection assays—with the use of chimeric constructs encompassing this region ligated to a luciferase reporter gene—revealed strong transcriptional activity. Comparison of the mouse, rat, and human AJ18 promoters revealed high sequence identity that included several responsive elements for proteins such as Runx2, NFB, Smads, Sp1, and Ets1.

The expression of AJ18 mRNA and protein at various stages of mouse development has revealed high levels in brain, kidney, and mineralized tissues during embryonic development (Jheon et al., 2002). In developing endochondral bone, AJ18 protein was stained strongly in proliferating and pre-hypertrophic chondrocytes, and in osteoblasts, with low or no staining in hypertrophic chondrocytes. Nuclear staining was also observed in differentiating cells that form the mineralized tissues of teeth. Notably, the expression of AJ18 was similar to the expression of BMP-7, consistent with its perceived role as a transcriptional factor that regulates developmental processes downstream of BMP-7. From the studies described above, AJ18 is strongly implicated as playing a role in osteogenesis. AJ18 may be competing with Runx2 for the same binding sites on target promoters during bone development, or may inhibit the transcription of target genes until the arrival of Runx2. The expression of AJ18 before Runx2 expression during mouse embryonic development would support the latter hypothesis (Jheon et al., 2001b). Generation of transgenic mice over-expressing AJ18 under the Col1a1 promoter is expected to provide clearer insights on the physiological role of AJ18. We would anticipate that these transgenic mice, not unlike the Runx2 and Osx knockout mice, will show a decrease in osteoblast differentiation and, thus, bone formation.

Zfp60
Differential display analysis of zinc finger genes expressed during the differentiation of mouse calvarial osteoblasts in our laboratory has led to the discovery of a gene fragment of the transcription factor Zfp60, which had initially been described as a transiently expressed gene during in vitro muscle differentiation (Perez et al., 1996). Zfp60 contains an N-terminal KRAB domain and 19 C2H2 zinc finger repeats. We found this gene to be transiently expressed during organogenesis in developing mouse embryos, predominantly in skin epithelium, at sites of epithelial-mesenchymal interactions (such as developing whisker follicles) and, notably, in early cartilage condensations and pre-hypertrophic chondrocytes (Ganss and Kobayashi, 2002). Expression of Zfp60 can be detected in multiple adult mouse tissues, with the highest mRNA expression in the epiphyseal growth plate of developing long bones, coinciding with the expression of known regulators of cartilage differentiation, such as Indian hedgehog (Ihh) and the receptor for parathyroid hormone (PTH) and related peptide (PTHrP). Further, Zfp60 expression precedes the expression of type X collagen as a marker of hypertrophic chondrocytes in vivo and in vitro. In vitro, over-expression of Zfp60 in chondrogenic ATDC5 cells leads to delayed chondrocyte differentiation (Ganss and Kobayashi, 2002). Therefore, Zfp60 may regulate the rate of transition from proliferating to hypertrophic chondrocytes, a critical step in long bone growth, by suppressing the transcription of currently unknown target genes via its KRAB domain.

NT2
The KRAB-zinc finger protein NT2 was recently identified by one-hybrid screening as a factor that binds to a 24-bp regulatory sequence in the type XI collagen (Col11a2) promoter (Tanaka et al., 2002). During embryonic development of long bones in mice, Col11a2 and NT2 are expressed in mutually exclusive regions, while the expression of type X collagen (Col10a1) and that of NT2 overlap. These observations suggest that NT2 inhibits the expression of Col11a2 as cartilage differentiation progresses and cells assume a more mature, hypertrophic phenotype.

Znf8
The involvement of a KRAB/C2H2 zinc finger protein in the BMP signaling/Smad pathway has been demonstrated recently (Jiao et al., 2002). Znf8 was isolated by a yeast-two-hybrid screening experiment with the regulatory Smad (R-Smad) protein Smad 1 used as bait. The primary structure of Znf8, containing an N-terminal KRAB domain and seven consecutive C2H2 zinc finger domains in the central portion of the predicted protein, suggests that this factor acts as a transcriptional repressor. Indeed, fusion of the full-length Znf8 protein to the GAL4 DNA-binding domain confirmed that Znf8 possesses intrinsic transcriptional repressor activity in mammalian cells. GST pull-down assays confirmed that Znf8 physically interacts with various Smad proteins, with the highest affinity for the BMP-associated Smad1 and Smad 5, but the Smad interaction domain in Znf8 has not been determined. Interestingly, Znf8 retains some of its repressor activity even in the absence of the KRAB domain, indicating that other as-yet-unidentified motifs in the protein may be involved in the down-regulation of target gene transcription. Alternatively, Znf8 may compete with a transcriptional activator for DNA binding, as suggested for AJ18 in its suppression of Runx2-mediated gene activation.

The bifunctional nature of regulatory transcription factors of the zinc finger gene family, with the potential to bind DNA and/or a variety of regulatory proteins through distinct zinc finger domains, appears to extend their potential to co-ordinate the responses to various signaling pathways, including BMP signaling and skeletal development. Three possible mechanisms of action for the regulation of Smad activity by zinc finger proteins have been suggested, based on the presence of these discrete DNA-binding and protein interaction domains (Jiao et al., 2002).

(3.2) KRüPPEL-RELATED GENES
Early analyses in Drosophila have identified the gene locus for the Krüppel (German for ‘cripple’) mutation as a crucial element for proper patterning and segmentation (Wieschaus et al., 1984). The identification of the cDNA sequence of the Krüppel gene (Preiss et al., 1985) revealed that Krüppel contains three consecutive C2H2 zinc finger motifs, linked by the conserved sequence TGEKPF/Y. A great many related Krüppel-type genes have since been identified in eukaryotic organisms (Tupler et al., 2001), including the family of Sp factors, Gli proteins, and the TGF-β-inducible early genes, TIEG-1 and TIEG-2. Certain members of these families, which have been implicated in skeletal and mineralized tissue development, are discussed in more detail below.

c-Krox
c-Krox was originally cloned from mouse NIH3T3 fibroblasts and was found to be predominantly expressed in skin (Galera et al., 1994), where it binds to specific sites in the Col1a1 and Col2a1 promoters (Galera et al., 1996). Although analysis of these data indicates that c-Krox regulates the expression of the type I collagen genes preferentially in skin and not in bone, c-Krox expression has more recently been detected in bone cells. There, it was implicated in the transcriptional regulation of the human biglycan gene (Heegaard et al., 1997), which is predominantly expressed in skeletal, connective, and epithelial tissues (Bianco et al., 1990).

Krox-20
Earlier studies have identified the transcription factor Krox-20 as a regulator of cell proliferation (Chavrier et al., 1988). Krox-20 is expressed in rhombomeres 3 and 5 at the mid/hindbrain border during murine embryonic development (Wilkinson et al., 1989), where it acts as a direct transcriptional activator for the homeobox-containing gene Hox2.8 (Sham et al., 1993). Targeted disruption of the Krox-20 gene in mice by homologous recombination has indeed resulted in specific developmental defects of rhombomeres 3 and 5 and early post-natal death (Schneider-Maunoury et al., 1993). Interestingly, the disruption of Krox-20 was also found to interfere with endochondral ossification, leading to a reduction in bone mineral density and size of long bones, mandibular deformities, and the lack of trabecular bone formation in growth plates (Levi et al., 1996a,b).

Krox-24
Krox-24 (also known as early growth response gene [egr-1] or Zif268) is a ubiquitously expressed transcription factor with three zinc finger motifs that has been implicated in a vast number of biological processes (Khachigian and Collins, 1998; Thiel and Cibelli, 2002), including tooth development (Karavanova et al., 1992) and the responses of cultured osteoblastic cells to retinoic acid (Suva et al., 1991) and mechanical stimulation (Ogata, 1997; Hatton et al., 2003). However, the roles of Krox-24/egr-1/Zif268 appear to be so diverse that it can hardly be regarded as a tissue-specific regulator of gene transcription.

Krox-26
Originally identified as the gene fragment Y150 from a rat incisor cDNA library (Matsuki et al., 1995), the full-length rat cDNA was designated Krox-26, due to a Krüppel-type arrangement of its C2H2 zinc finger motifs (Lee et al., 1997). The murine Krox-26 cDNA was subsequently cloned from P19 embryonic carcinoma cells in our laboratory. Krox-26 contains five consecutive C2H2 zinc finger repeats and is therefore expected to act as a DNA-binding regulator of gene transcription. We have recently conducted several studies to determine the expression patterns of Krox-26 mRNA and protein during mouse development. These studies revealed that the 2.4-kb Krox-26 mRNA transcript is maximally expressed during a period of active organ formation in mouse embryos. Further, immunohistochemistry experiments have shown that, in the developing murine tooth organs, Krox-26 is expressed in dental epithelium during early stages of tooth development and specifically in secretory-stage ameloblasts of three- to four-week-old mice (Ganss et al., 2002). These results suggest that Krox-26 is a novel molecular regulator of tooth formation and/or amelogenesis. In a more extensive immunohistochemical study, Krox-26 protein was found in several mesenchymal tissues during mouse embryonic development, but predominantly in developing craniofacial bones and dental organs. A Target Detection Assay (TDA) (Thiesen and Bach, 1990), with the use of bacterially expressed mouse Krox-26 protein, has shown that Krox-26 binds DNA at the preferred site cCAATg, suggesting that Krox-26 may be involved in the transcriptional regulation of target genes through CCAAT-box elements (Teo et al., 2003). Our experiments screening for upstream regulators of Krox-26 expression in mouse mandibular organ explant cultures have shown that the expression of Krox-26 is not responsive to BMP-2 or -4 or to FGF-4 or -8 stimulation (unpublished), suggesting that Krox-26 may act upstream of these odontogenic signaling molecules or be regulated by other signaling pathways during tooth formation. We have recently isolated and characterized the human KROX-26 orthologue and showed that KROX-26 is expressed as a single 2.4-kb mRNA in developing dental epithelium and osteoblasts of the craniofacial skeleton (Gao et al., 2003). The conceptually translated Krox-26 protein sequence is highly conserved between mice and humans. We have localized the KROX-26 gene to human chromosome 10q11.2, a region that coincides with a novel gene locus for agenesis of permanent teeth, known as He-Zhao deficiency (Liu et al., 2001). It remains to be demonstrated if KROX-26 is a candidate gene for this developmental disorder.

Sp family
The founding member of the Sp family of zinc finger genes, Sp1, was initially named after the protein purification protocol that involved Sephacryl and phosphocellulose columns (Kadonaga et al., 1987). The Sp family currently consists of the Sp factors, Sp1 to Sp8, and the Krüppel-like factors, KLF1 to KLF16 (Philipsen and Suske, 1999; Bouwman and Philipsen, 2002; Kaczynski et al., 2003). Due to the sequence similarity in their zinc finger domains, members in this family recognize and bind to similar GC-rich target sequences on DNA, which occur frequently in the promoter of many different ubiquitously expressed or tissue-specific target genes. Although the DNA-binding sites for the Sp/KLF factors are at least similar if not identical, functional differences exist between individual family members. These differences must be attributed to structural and functional differences in the sequences outside of the zinc finger domain. Most Sp/KLF factors themselves are expressed ubiquitously or in multiple tissues, with the exception of Sp7, which was recently described as Osterix (Nakashima et al., 2002) and is essentially restricted to cells of the osteoblast lineage. The function of Sp3 and Sp7 in tooth formation and skeletogenesis, respectively, has recently been demonstrated by targeted disruption of these genes in mice.

Sp3
Sp3 is ubiquitously expressed during mouse embryonic development and has been associated with the transcriptional activation of a large number of potential target genes (Suske, 1999). To understand the biological function of Sp3 in more detail, Bowman et al.(2000) generated mice deficient in this transcription factor by homologous recombination in embryonic stem (ES) cells. Sp3 mutant mice develop in utero without any gross malformations, but invariably die within 10 minutes after birth due to respiratory failure. In spite of the ubiquitous expression of Sp3 in wild-type animals, a detailed analysis of Sp3-deficient animals revealed several specific defects in tooth and bone formation. In particular, histological analysis showed that the formation of the enamel layer of developing teeth was severely impaired. mRNA transcripts for the ameloblast-specific amelogenin and ameloblastin genes could not be detected in Sp3-/- mice, while mRNA expression levels for the odontoblast-associated genes dentin matrix protein 1 (DMP1) and tuftelin were unchanged. These results suggest a specific defect in ameloblast function and enamel matrix production that is not the result of impaired dentinogenesis. In a separate study, several skeletal malformations were identified in Sp3-deficient mice (Gollner et al., 2001), including mineralization defects in vertebral bodies, sternum, and the xiphoid process, as well as in skull bones and the craniofacial skeleton. The expression of osteocalcin mRNA was significantly reduced, while mRNA levels for Runx2/Cbfa1 were not affected by the lack of Sp3. The retinoic-acid-induced osteogenic differentiation of Sp3-deficient embryonic stem cells was also impaired when compared with ES cells derived from wild-type animals.

Sp7 (Osterix)
Upon the exposure of C2C12 muscle progenitor cells to BMP-2, these cells are directed toward the osteoblast lineage (Katagiri et al., 1994). Osterix (Osx) was identified as an early induced gene in osteogenic-directed C2C12 cells via a modified subtractive hybridization technique (Nakashima et al., 2002). Osx encodes a 46-kDa protein containing three C2H2 zinc finger motifs located near the C-terminus that share a high degree of sequence conservation with the Sp family of C2H2 zinc finger proteins. Osx binds specifically to G/C-rich dsDNA, possesses strong transcriptional ability upstream of the zinc finger motifs, and is localized in the nucleus, suggesting that Osx indeed functions as a typical transcription factor. The role of Osx during osteoblastic differentiation appears to involve its ability to up-regulate the expression of osteocalcin and Col1a1 mRNA. Moreover, the expression of Osx during mouse embryonic development is restricted to transient expression in differentiating chondrocytes, mesenchymal cells of the tooth germ, and strong expression in bone-forming cells, although Osx does not appear to be expressed in any adult tissues in humans (Gao et al., in press).

Taken together, the evidence suggested the involvement of Osx during skeletal development. However, the magnitude of the importance and influence of Osx on the differentiation of osteoblasts was not realized until Osx-null mice were generated (Fig. 4). The Osx- and Runx2-null mice share a similar phenotype, since both mutants completely lack differentiated osteoblasts and, thus, bone. The most notable difference is that in Osx-null mice, Runx2 is expressed seemingly without alteration, whereas expression of Osx was absent in Runx2-null mice; this suggests that Osx functions downstream of Runx2. Although knockouts of both Runx2 and Osx resulted in mice lacking bone, it now appears that Runx2 is also involved in the differentiation of cartilage (Inada et al., 1999). Notably, Osx-deficient mice still form mineralized cartilage (Fig. 4), suggesting a specific function for this zinc finger transcription factor in osteoblast differentiation, although Osx expression can be induced by BMP-2 in chondrocytes in vitro (Yagi et al., 2003).

View larger version (43K): [in this window] [in a new window]   Figure 4. Phenotype of osterix (Sp7)-deficient mice. Staining of skeletal preparations from embryonic day 15.5 (E15.5) and newborn homozygous mutant mice with alcian blue and alizarin red indicated a virtual absence of mineralization in all facial and skull bones formed by intramembranous ossification and a general deficiency of osteoblast differentiation. Reproduced with permission from Nakashima et al.(2002).

TIEG family
TIEG (TGF-β-inducible early gene) was initially identified by differential display-PCR as a gene fragment that is up-regulated in human osteoblastic cells within one hour after treatment with TGF-β (Subramaniam et al., 1995). TIEG is also responsive to other TGF-β family members such as BMP-2, BMP-4, and activin, as well as epidermal growth factor, but only at much higher concentrations than required for TGF-β (Subramaniam et al., 1998). TIEG possesses three C2H2 motifs and several proline-rich Src-homology-3 (SH3) binding motifs (Subramaniam et al., 1995). As a putative transcription factor, TIEG has been shown to be rapidly translocated to the nucleus upon TGF-β treatment (Subramaniam et al., 1998), and a consensus DNA-binding site consisting of the sequence 5'-GGTGTG-3' has been identified (Chrisman and Tindall, 2003). Furthermore, TIEG contains repressor domains that are known to repress transcription in a heterologous GAL-4-based transcriptional assay (Cook et al., 1999). The TIEG gene was discovered to encode for two proteins (TIEG and Early Growth Response [EGR]-) that are expressed from alternative promoters; the use of alternative first exons results in TIEG having 12 unique amino acids on its N-terminus (Fautsch et al., 1998). TIEG represents the predominant species in many tissues and cell types examined. The over-expression of TIEG mimics the effects of TGF-β in human osteosarcoma MG-63 cells, including increased alkaline phosphatase activity, decreased levels of osteocalcin mRNA and protein, and decreased cell proliferation (Hefferan et al., 2000). TIEG/EGR- is thus believed to act as a transcription factor in the TGF-β pathway. Specifically, it has been suggested that TIEG enhances Smad signaling by a dual mechanism involving both the repression of the inhibitory Smad7 as well as the activation of Smad2 (Johnsen et al., 2002).

A second member of the TIEG subfamily, called TIEG2, was subsequently identified (Cook et al., 1998); thus, TIEG is also referred to as TIEG1. TIEG2 is ubiquitously expressed, with the highest expression in the pancreas and muscle. To date, the involvement of TIEG2 during skeletal development is unknown. Through the analyses of TIEG1 and TIEG2, three separate putative repression domains (R1, 10-amino-acid sequence; R2, 12-amino-acid sequence; and R3, 80-amino-acid sequence) were identified in both proteins, revealing a new subfamily of TIEGs.

(3.3) OTHER ZINC FINGER FACTORS
Schnurri
The Drosophila zinc finger gene schnurri (shn) is a downstream component of decapentaplegic (dpp) signaling (Arora et al., 1995; Grieder et al., 1995; Staehling-Hampton et al., 1995), which has been recognized as the Drosophila equivalent of mammalian BMP signaling pathway. Several mammalian genes are structurally related to schnurri, but, due to the apparent evolutionary divergence of this gene, a true mammalian shn orthologue may not be readily identifiable.

CRYBP1
The -A-crystallin binding protein 1 (CRYBP1) was originally identified as a regulator of the ocular lens-specific -A-crystallin gene (Nakamura et al., 1990). CRYBP1 has been suggested as a homologue of the Drosophila shn gene (Tanaka et al., 2000). The analysis of the gene structure and expression of CRYBP1 revealed an arrangement of two widely spaced C2H2 zinc finger domains at the C-terminal and N-terminal ends of the protein, which are likely to bind to the same DNA sequence (Fan and Maniatis, 1990). The primary CRYBP1 mRNA transcript is alternatively spliced and produces two proteins that contain either zinc finger domain. Recently, CRYBP1 was identified as a protein that binds to the type II collagen (Col2a1) enhancer element (Tanaka et al., 2000). In this study, an inverse correlation between the expression of CRYBP1 and Col2a1 mRNA was found during the chondrogenic differentiation of ATDC5 cells in vitro and in mouse embryos in vivo, suggesting that CRYBP1 acts as a sequence-specific repressor of Col2a1 expression. Interestingly, the binding to this enhancer sequence is mediated by the splice variant containing the C-terminal (C-ZF), but not the N-terminal (N-ZF) zinc finger domain of CRYBP1. The Col2a1 enhancer element has been identified previously as a target for transcriptional activation by the high-mobility group (HMG) transcription factor Sox9 (Lefebvre et al., 1997). CRYBP1, via its C-ZF domain, suppresses the Sox9-mediated activation of Col2a1 transcription by competing with Sox9 for binding to the Col2a1 enhancer.

CIZ
CIZ, Cas130-interacting zinc finger protein, was originally discovered as a zinc finger protein that shuttles between focal adhesion complexes and the nucleus, where it enhances the transcription of the matrix metalloproteinase (MMP) genes MMP-1, -2, and -7 (Nakamoto et al., 2000). CIZ exists in several splice variants that contain five, six, or eight C2H2 zinc finger domains. It was subsequently identified as a component of nuclear matrix protein (NMP) complexes located within specific nuclear matrix subdomains in osteoblasts (Feister et al., 2000). Over-expression of CIZ in MC3T3-E1 osteoblast cells increased the number of adhesion plaques and stimulated type I collagen gene transcription, most likely through a direct interaction with an inverted CIZ binding site (TTTTTC) in the Col1a1 promoter (Furuya et al., 2000; Thunyakitpisal et al., 2001). A recent study has investigated the effect of CIZ on BMP-2-induced osteoblastic differentiation in MC3T3-E1 cells. While, in the absence of BMP-2, CIZ slightly stimulated the promoter activity and expression of the osteoblast transcription factor Runx-2 (Cbfa1), over-expression of CIZ inhibited the BMP-2-induced stimulation of several bone-associated genes such as alkaline phosphatase, osteocalcin, and type I collagen. CIZ also interfered with BMP-induced activation of transcription by Smad-1 and Smad-5 (Shen et al., 2002), implying that CIZ is a negative regulator of BMP signaling in osteoblasts.

YY1
Yin Yang 1 (YY1), another ubiquitously expressed nuclear matrix protein containing five C2H2 zinc finger domains, was originally identified as a repressor of the adeno-associated virus P5 promoter (Shi et al., 1991). Since then, YY1 has been implicated in the activation or repression of transcription for myriad viral and eukaryotic target genes, often through interaction with other transcription factors such as Sp1 (Seto et al., 1993) or c-myc (Shrivastava et al., 1993). YY1 recognizes its cognate DNA-binding sites with a high degree of sequence variability (Hyde-DeRuyscher et al., 1995). The first reports implicating YY1 in the function of osteoblasts demonstrated a YY1-mediated transactivation of the osteocalcin gene through a vitamin D response element (Guo et al., 1997) and a YY1 binding site in the human BSP promoter (Kerr et al., 1997). More recent studies have concluded that YY1 engages in multiple interactions in the promoter of the histone H4 gene and thus regulates the architecture of the nuclear matrix and the chromatin structure (Last et al., 1999; Lian et al., 2001). Perhaps not surprisingly, targeted disruption of YY1 in mice resulted in peri-implantation lethality, indicating its fundamental role in development (Donohoe et al., 1999). The activity of YY1 has been shown to be regulated by post-translational modifications that are required for chromatin remodeling, such as acetylation and de-acetylation (Yao et al., 2001), and by O-linked N-acetylglucosaminylation (Hiromura et al., 2003). A recent report has demonstrated that YY1 interferes with TGF-β and BMP-induced cell differentiation by interacting with downstream effectors such as Smad-4 via its zinc finger domains and by competing for a Smad binding element on DNA (Kurisaki et al., 2003). Thus, YY1 can use a subset of its zinc finger domains for DNA binding, while another set of zinc fingers is engaged in protein-protein interactions. Interestingly, the osteoblast ‘master’ regulator Runx2 (Cbfa1) has also been defined as a nuclear matrix protein (NMP2) and has been implicated, together with CIZ and YY1, in mediating the complex effects of nuclear matrix proteins on skeletal gene expression (Bidwell et al., 2001).

OAZ
The Olf-1/EBF associated zinc finger gene (OAZ) has been implicated in olfactory epithelium and B-lymphocyte development (Tsai and Reed, 1997, 1998) and was recently identified as a mediator of BMP signaling that binds to a BMP response element (BRE) in the Xenopus Xvent-2 gene promoter (Hata et al., 2000). OAZ represents a 1224-amino-acid protein containing 30 C2H2 zinc finger domains that are arranged in several clusters. The OAZ mRNA is ubiquitously expressed during Xenopus early embryonic development, and its human orthologue is highly expressed in multiple adult tissues, but predominantly in skeletal muscle. OAZ binds to the Xvent-2 BRE directly via its zinc fingers 6 to 13, even in the absence of BMP signaling. Zinc fingers 14 to 19 interact directly with the MH2 domain of Smad 1 and Smad4, but not Smad 2, indicating that OAZ is primarily involved in regulating the activity of Smads that are associated with BMP signaling. However, the modulation of BMP responses by OAZ appears to be dependent on the promoter context, since OAZ stimulates the transactivation of the BRE in the Xvent-2 promoter, but inhibits the response to BMP signaling in the BMP-responsive region of the Tlx-2 gene promoter.

	A Concluding Note

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The relatively simplistic view of zinc finger proteins binding DNA on the one hand and interacting with the basal transcription machinery on the other has certainly unraveled some important principles about these multifunctional proteins. However, a much more complex mode of action can be anticipated as additional zinc finger proteins continue to be characterized in more detail. That zinc finger genes are functionally important regulators of skeletogenesis is evident from phenotypic anomalies already discussed for only a few family members. The Table attempts to summarize the current state of knowledge without any claim to completeness. We apologize to the many authors whose contributions to this field could not be mentioned explicitly due to space limitations.

	The Future

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Notes added in proof: Ravasi et al.(2003) describe the characterization of Sp8, a new member of the Sp family of transcriptional regulators, and the identification of five new RING-H2 proteins.

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Critical Reviews in Oral Biology & Medicine, Vol. 15, No. 5, 282-297 (2004)
DOI: 10.1177/154411130401500504


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