DSPP mutation in dentinogenesis imperfecta Shields type II

Zhang, Xiaohai; Zhao, Jun; Li, Changfu; Gao, Shan; Qiu, Changchun; Liu, Ping; Wu, Guoli; Qiang, Boqin; Lo, Wilson H.Y.; Shen, Yan

doi:10.1038/84765

Cited by 328 publications

(199 citation statements)

References 10 publications

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“…There was little change in the amount of h1 probe-Dlx5 complex (Fig. 4D, lane [4][5][6], but the h2 probe-Dlx5 complex decreased with increase of the Msx2 protein (Fig. 4D, lanes 11-13).…”

Section: -G)mentioning

confidence: 99%

“…DSPP is synthesized as a single polypeptide and then cleaved into three peptides, dentin sialoprotein (DSP), dentin glycoprotein (DGP), and dentin phosphoprotein (DPP) (2,3). Evidence from human and mouse genetic studies indicates that DSPP is important for dentin mineralization (4); mutations of the DSPP gene have been identified in human families with dentinogenesis imperfecta II and III (5,6), in whom dentin mineralization is defective. Moreover, Dspp-null mice show dentin mineralization defects that are very similar to human dentinogenesis imperfecta III.…”

Section: Dentin Sialophosphoprotein (Dspp)mentioning

confidence: 99%

“…The cleavage of DSPP into smaller proteins has been proposed to be an activation step (5). The failure of the cleavage process is a critical cause of defects in developmental dentin formation (3).…”

Section: Dentin Sialophosphoprotein (Dspp)mentioning

confidence: 99%

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The Canonical BMP Signaling Pathway Plays a Crucial Part in Stimulation of Dentin Sialophosphoprotein Expression by BMP-2

Cho

Yoon

Woo

et al. 2010

Journal of Biological Chemistry

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Dentin sialophosphoprotein (DSPP), a typical dentin-specific protein, is mainly expressed in the dentin extracellular matrix and plays a role in dentin mineralization. BMP-2 provides a strong signal for differentiation and mineralization of odontoblasts and osteoblasts. Previously, BMP-2 treatment is reported to stimulate Dspp expression in the MD10-F2 pre-odontoblast cells through activation of the heterotrimeric transcription factor Y (NF-Y). The canonical BMP signaling pathway is known to contribute greatly to biomineralization, however, it is not known whether it is involved in Dspp expression. Here, we investigated this question. Activation of the canonical BMP-2 signaling pathway in MDPC-23, preodontoblast cell, by overexpression of constitutively active Smad1/5 or downstream transcription factors Dlx5 and Runx2 stimulated Dspp expression. Conversely, knockdown of each element with siRNA significantly blocked the BMP-2-induced Dspp expression. To test whether these transcription factors downstream of BMP-2 are directly involved in regulating Dspp, we analyzed the mouse Dspp promoter. There are 5 well conserved homeodomain binding elements, H1 to H5, in Dspp proximal promoter regions (؊791 to ؉54). A serial deletion of H1 and H2 greatly changed basal promoter activity and responsiveness to Dlx5 or Msx2. However, further deletions did not change the responsiveness to Dlx5 or Msx2. H1 and H2 sites can be suggested as specific response elements of Dlx5 and Msx2, respectively, based on their promoter activity modulation. Thus, the canonical BMP-2 signaling pathway plays a crucial part in the regulation of Dspp expression through the action of Smads, Dlx5, Runx2, and Msx2. Dentin sialophosphoprotein (DSPP)2 is a major non-collagenous dentin matrix protein and is mainly expressed by odontoblasts (1). DSPP is synthesized as a single polypeptide and then cleaved into three peptides, dentin sialoprotein (DSP), dentin glycoprotein (DGP), and dentin phosphoprotein (DPP) (2, 3). Evidence from human and mouse genetic studies indicates that DSPP is important for dentin mineralization (4); mutations of the DSPP gene have been identified in human families with dentinogenesis imperfecta II and III (5, 6), in whom dentin mineralization is defective. Moreover, Dspp-null mice show dentin mineralization defects that are very similar to human dentinogenesis imperfecta III.DSPP is a member of the small integrin-binding ligand N-linked glycoproteins (SIBLINGS) family of proteins, which also includes bone sialoprotein, osteopontin, dentin matrix protein 1, and matrix extracellular phosphoglycoprotein. The genes encoding these proteins are clustered on chromosome 4q21 in humans and 5q in mouse, and the proteins are commonly involved in dentin and bone mineralization and share an acidic serine-and aspartate-rich motif (7).The cleavage of DSPP into smaller proteins has been proposed to be an activation step (5). The failure of the cleavage process is a critical cause of defects in developmental dentin formation (3). DSP is in the N-te...

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“…There was little change in the amount of h1 probe-Dlx5 complex (Fig. 4D, lane [4][5][6], but the h2 probe-Dlx5 complex decreased with increase of the Msx2 protein (Fig. 4D, lanes 11-13).…”

Section: -G)mentioning

confidence: 99%

Section: Dentin Sialophosphoprotein (Dspp)mentioning

confidence: 99%

See 1 more Smart Citation

The Canonical BMP Signaling Pathway Plays a Crucial Part in Stimulation of Dentin Sialophosphoprotein Expression by BMP-2

Cho

Yoon

Woo

et al. 2010

Journal of Biological Chemistry

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“…As of this writing, eight mutations have been identified in the human DSPP gene that cause hereditary dentin defects (3)(4)(5)(6)(7). In each case, the phenotype is inherited in an autosomal dominant pattern and is usually limited to the teeth.…”

mentioning

confidence: 99%

Porcine Dentin Sialoprotein Is a Proteoglycan with Glycosaminoglycan Chains Containing Chondroitin 6-Sulfate

Yamakoshi

Fukae

et al. 2005

Journal of Biological Chemistry

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Dentin sialoprotein (DSP) is a glycoprotein that is critical for proper tooth dentin formation, but little is known about the nature of its carbohydrate attachments and other post-translational modifications. We have isolated DSP from pig dentin and demonstrate that it is a proteoglycan. Polyclonal antibodies were raised in chicken against recombinant pig DSP, and used to identify native DSP in fractions of tooth dentin proteins extracted from developing pig molars. Amino acid analyses and characterization of lysylendopeptidase cleavage products confirmed that the purified protein was DSP, and that Arg 391 is at the DSP C terminus. On SDS-PAGE and on urea gels, DSP appeared as a smear extending from 280 to 100 kDa, but in the presence of ␤-mercaptoethanol the top of the DSP smear disappeared. The high molecular weight material was likely comprised of covalent DSP dimers connected by a disulfide bridge at Cys 205 . Oligosaccharides were released from DSP following N-and O-linked glycosidase digestions, but these digestions had little effect on the apparent molecular weight of DSP on SDS-PAGE, when compared with the significant reduction following chondroitinase ABC digestion. Glycosaminoglycanases with assorted glycosaminoglycan (GAG) cleavage specificities coupled with Western analyses of the cleaved GAG "stubs" demonstrated that the DSP GAG attachments contain chondroitin 6-sulfate, but not keratan sulfate, heparan sulfate, chondroitin, or chondroitin 4-sulfate. DSP binds biotin-labeled hyaluronic acid, and such binding is inhibited by the addition of unlabeled hyaluronic acid. We conclude that DSP is a proteoglycan and that GAG attachments are the predominant structural feature of porcine DSP.The dentin sialophosphoprotein gene (DSPP) 1 on human chromosome 4q21.3 encodes the two major noncollagenous proteins in tooth dentin: dentin sialoprotein (DSP) and dentin phosphoprotein (DPP) (1, 2), and these proteins are critical for proper dentin formation. As of this writing, eight mutations have been identified in the human DSPP gene that cause hereditary dentin defects (3-7). In each case, the phenotype is inherited in an autosomal dominant pattern and is usually limited to the teeth. Occasionally the condition is associated with progressive neurosensory high frequency hearing loss (DFNA39/DGI1, MIM 605594). In addition, DSPP-null mice developed dentin defects in the absence of other symptoms (8).Whereas it is known that DSPP gene products are essential for normal dentin biomineralization, DSP structural features are only partially characterized, and its functions are unknown.Much of our current understanding of the structure and function of dentin sialoprotein comes from studies of the rat protein (9 -11). Rat DSP is the N-terminal portion of DSPP and is generated by proteolytic cleavages, primarily after Tyr 421 but also following His 406 (12). The molecular mass of the major rat DSP component, which contains 29.6% carbohydrate, was determined by sedimentation equilibrium analysis to be 52.57 kDa (13), although t...

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“…The effect of gremlin on Dspp expression in pulp cells was determined in murine dental pulp cells in vitro. The importance of Dspp in dentinogenesis has been demonstrated by the observations that mutations in the Dspp gene are associated with dentinogenesis imperfecta in humans [47], and Dspp gene knockout mice show hypomineralization of dentin (widening of predentin) [48]. Transgenic mice overexpressing active TGF-β1 driven by the Dspp promoter, displayed decreased mineralization of enamel and dentin, abnormal dentin formation, and downregulated Dspp mRNA expression [49].…”

Section: In Vitro Resultsmentioning

confidence: 99%

Transgenic Overexpression of Gremlin Results in Developmental Defects in Enamel and Dentin in Mice

Nagatomo

Tompkins

Fong

et al. 2008

Connective Tissue Research

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Bone morphogenetic proteins (BMPs) and BMP antagonists play a crucial role in the regulation of tooth development. One of the BMP extracellular antagonists, gremlin, is a highly conserved 20.7-kDa glycoprotein. Previously, researchers reported that transgenic mice overexpressing gremlin under the control of the osteocalcin promoter (gremlin OE) exhibit a skeletal phenotype and tooth fragility. To further define the tooth phenotype, teeth and surrounding supporting tissues, obtained from gremlin OE at ages of 4 weeks, 2 months, and 4 months, were examined. The histological results demonstrate that gremlin OE exhibit an enlarged pulp chamber with ectopic calcification and thinner dentin and enamel compared with wild-type control. In vitro studies using murine pulp cells revealed that gremlin inhibited BMP-4 mediated induction of Dspp. These data provide evidence that balanced interactions between BMP agonists/antagonists are required for proper development of teeth and surrounding tissues. It is clear that these interactions require further investigation to better define the mechanisms controlling tooth root formation (pulp, dentin, cementum, and surrounding tissue) to provide the information needed to successfully regenerate these tissues.

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DSPP mutation in dentinogenesis imperfecta Shields type II

Cited by 328 publications

References 10 publications

The Canonical BMP Signaling Pathway Plays a Crucial Part in Stimulation of Dentin Sialophosphoprotein Expression by BMP-2

The Canonical BMP Signaling Pathway Plays a Crucial Part in Stimulation of Dentin Sialophosphoprotein Expression by BMP-2

Porcine Dentin Sialoprotein Is a Proteoglycan with Glycosaminoglycan Chains Containing Chondroitin 6-Sulfate

Transgenic Overexpression of Gremlin Results in Developmental Defects in Enamel and Dentin in Mice

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