Nucleus-targeted Dmp1 transgene fails to rescue dental defects in Dmp1 null mice

Abstract

A protein involved in tooth mineralization, although found in the nucleus, does not seem to play a role there during tooth formation. Dentin matrix protein 1 (DMP1) is present both in the nucleus and in the cytoplasm of odontoblasts, cells that form part of the dental pulp. To examine DMP1's role during embryonic tooth development, a team led by Jian-Quan Feng of the Texas A&M University Baylor College of Dentistry, USA, bred transgenic mice that only express DMP in the nucleus. These mice displayed dental defects and delayed tooth eruption similar to the defects seen in mouse strains with no functional versions of DMP1 in the nucleus or the cytoplasm. A human patient with a DMP1 gene mutation that causes only nuclear protein localization also exhibited tooth abnormalities consistent with rickets.

Keywords

autosomal recessive hypophosphatemic rickets / dentin matrix protein 1 / development / odontoblast / odontogenesis

References

[1] Fisher LW, Torchia DA, Fohr B. Flexible structures of SIBLING proteins, bone sialoprotein, and osteopontin. Biochem Biophys Res Commun, 2001, 280(2): 460-465.

[2] Feng JQ, Ward LM, Liu S. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat Genet, 2006, 38(11): 1310-1315.

[3] Jiang B, Cao Z, Lu Y. DMP1 C-terminal mutant mice recapture the human ARHR tooth phenotype. J Bone Miner Res, 2010, 25(10): 2155-2164.

[4] Lu Y, Ye L, Yu S. Rescue of odontogenesis in Dmp1-deficient mice by targeted re-expression of DMP1 reveals roles for DMP1 in early odontogenesis and dentin apposition in vivo. Dev Biol, 2007, 303(1): 191-201.

[5] Ye L, MacDougall M, Zhang S. Deletion of dentin matrix protein-1 leads to a partial failure of maturation of predentin into dentin, hypomineralization, and expanded cavities of pulp and root canal during postnatal tooth development. J Biol Chem, 2004, 279(18): 19141-19148.

[6] Ye L, Zhang S, Ke H. Periodontal breakdown in the Dmp1 null mouse model of hypophosphatemic rickets. J Dent Res, 2008, 87(7): 624-629.

[7] George A, Sabsay B, Simonian PA. Characterization of a novel dentin matrix acidic phosphoprotein. Implications for induction of biomineralization. J Biol Chem, 1993, 268(17): 12624-12630.

[8] Feng JQ, Huang H, Lu Y. The dentin matrix protein 1 (Dmp1) is specifically expressed in mineralized, but not soft, tissues during development. J Dent Res, 2003, 82(10): 776-780.

[9] Fen JQ, Zhang J, Dallas SL. Dentin matrix protein 1, a target molecule for Cbfa1 in bone, is a unique bone marker gene. J Bone Miner Res, 2002, 17(10): 1822-1831.

[10] He G, Dahl T, Veis A. Nucleation of apatite crystals in vitro by self-assembled dentin matrix protein 1. Nat Mater, 2003, 2(8): 552-558.

[11] Gajjeraman S, Narayanan K, Hao J. Matrix macromolecules in hard tissues control the nucleation and hierarchical assembly of hydroxyapatite. J Biol Chem, 2007, 282(2): 1193-1204.

[12] Gericke A, Qin C, Sun Y. Different forms of DMP1 play distinct roles in mineralization. J Dent Res, 2010, 89(4): 355-359.

[13] Tartaix PH, Doulaverakis M, George A. In vitro effects of dentin matrix protein-1 on hydroxyapatite formation provide insights into in vivo functions. J Biol Chem, 2004, 279(18): 18115-18120.

[14] Wu H, Teng PN, Jayaraman T. Dentin matrix protein 1 (DMP1) signals via cell surface integrin. J Biol Chem, 2011, 286(34): 29462-29469.

[15] Eapen A, Ramachandran A, Pratap J. Activation of the ERK1/2 mitogen-activated protein kinase cascade by dentin matrix protein 1 promotes osteoblast differentiation. Cells Tissues Organs, 2011, 194(2/3/4): 255-260.

[16] Narayanan K, Ramachandran A, Hao J. Dual functional roles of dentin matrix protein 1. Implications in biomineralization and gene transcription by activation of intracellular Ca²⁺ store. J Biol Chem, 2003, 278(19): 17500-17508.

[17] Ravindran S, Narayanan K, Eapen AS. Endoplasmic reticulum chaperone protein GRP-78 mediates endocytosis of dentin matrix protein 1. J Biol Chem, 2008, 283(44): 29658-29670.

[18] Braut A, Kalajzic I, Kalajzic Z. Col1α1-GFP transgene expression in developing incisors. Connect Tissue Res, 2002, 43(2/3): 216-219.

[19] Qin C, Brunn JC, Cook RG. Evidence for the proteolytic processing of dentin matrix protein 1. Identification and characterization of processed fragments and cleavage sites. J Biol Chem, 2003, 278(36): 34700-34708.

[20] Moses KD, Butler WT, Qin C. Immunohistochemical study of small integrin-binding ligand, N-linked glycoproteins in reactionary dentin of rat molars at different ages. Eur J Oral Sci, 2006, 114(3): 216-222.

[21] Wang X, Wang S, Lu Y. FAM20C plays an essential role in the formation of murine teeth. J Biol Chem, 2012, 287(43): 35934-35942.

[22] Fisher LW, Stubbs JT 3rd, Young MF. Antisera and cDNA probes to human and certain animal model bone matrix noncollagenous proteins. Acta Orthop Scand Suppl, 1995, 266: 61-65.

[23] Lu Y, Yuan B, Qin C. The biological function of DMP-1 in osteocyte maturation is mediated by its 57-kDa C-terminal fragment. J Bone Miner Res, 2011, 26(2): 331-340.

[24] Farrow EG, Davis SI, Ward LM. Molecular analysis of DMP1 mutants causing autosomal recessive hypophosphatemic rickets. Bone, 2009, 44(2): 287-294.

[25] Turan S, Aydin C, Bereket A. Identification of a novel dentin matrix protein-1 (DMP-1) mutation and dental anomalies in a kindred with autosomal recessive hypophosphatemia. Bone, 2010, 46(2): 402-409.

[26] Prasad M, Butler WT, Qin C. Dentin sialophosphoprotein in biomineralization. Connect Tissue Res, 2010, 51(5): 404-417.

[27] Zhu Q, Gibson MP, Liu Q. Proteolytic processing of dentin sialophosphoprotein (DSPP) is essential to dentinogenesis. J Biol Chem, 2012, 287(36): 30426-30435.

[28] Wang S, Huang Y, Qin C. Nuclear DMP1 (nuDMP1) is generated by alternative initiation of translation, 2013 Seattle, WA

[29] Siyam A, Wang S, Qin C. Nuclear localization of DMP1 proteins suggests a role in intracellular signaling. Biochem Biophys Res Commun, 2012, 424(3): 641-646.

[30] Sun Y, Prasad M, Gao T. Failure to process dentin matrix protein 1 (DMP1) into fragments leads to its loss of function in osteogenesis. J Biol Chem, 2010, 285(41): 31713-31722.

[31] Sun Y, Lu Y, Chen L. DMP1 processing is essential to dentin and jaw formation. J Dent Res, 2011, 90(5): 619-624.