The <i>Prx1</i> Homeobox Gene is Critical for Molar Tooth Morphogenesis

Mitchell, Jana M.; Hicklin, David M.; Doughty, P.M.; Hicklin, J.; Dickert, J.W.; Tolbert, S.M.; Peterková, Renata; Kern, Michael J.

doi:10.1177/154405910608501003

Cited by 28 publications

(24 citation statements)

References 29 publications

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“…These results were unexpected, as previous loss-of-function genetic mouse model studies have demonstrated the indispensable roles of these molecules [Satokata and Maas, 1994;Peters et al, 1998;D'Souza et al, 1999;Shibaguchi et al, 2003;Mitchell et al, 2006;Mitsiadis et al, 2008;Denaxa et al, 2009] in regulating early tooth development. Expression of these genes may peak during bud stage and start to decline beyond cap stage, which may explain why we saw no change in their expression levels between FDMCs (mostly bell stage) and ADMCs.…”

Section: Discussioncontrasting

confidence: 39%

Inductive Ability of Human Developing and Differentiated Dental Mesenchyme

Zheng

Warotayanont

Stahl

et al. 2013

Cells Tissues Organs

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The development of cell-based therapeutic strategies to bioengineer tooth tissue is a promising approach for the treatment of lost or damaged tooth tissue. The lack of a readily available cell source for human dental epithelial cells (ECs) severely constrains the progress of tooth bioengineering. Previous studies in model organisms have demonstrated that developing dental mesenchyme can instruct nondental epithelium to differentiate into enamel-forming epithelium. In this study, we characterized the ability of fetal and adult human dental mesenchyme to promote differentiation of human embryonic stem cell (hESC)-derived ECs (ES-ECs) into ameloblast-lineage cells. ES-ECs were co-cultured either with human fetal dental mesenchymal cells (FDMCs) or with adult dental mesenchymal cells (ADMCs) in either a three-dimensional culture system, or in the renal capsules of SCID mice. When co-cultured with FDMCs in vitro, ES-ECs polarized and expressed amelogenin. Tooth organ-like structures assembled with epithelium and encased mesenchyme and developing enamel-like structures could be detected in the complexes resulting from in vitro and ex vivo co-culture of ES-ECs and FDMCs. In contrast, co-cultured ES-ECs and ADMCs formed amorphous spherical structures and occasionally formed hair. Transcription factors were significantly upregulated in FDMCs compared to ADMCs including MSX1, GLI1, LHX6, LHX8,LEF1 and TBX1. In summary, FDMCs but not ADMCs had the capacity to induce differentiation of ES-ECs into ameloblast lineage cells. Further characterization of the functional differences between these two types of dental mesenchyme could enable reprogramming of ADMCs to enhance their odontogenic inductive competence.

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Section: Discussioncontrasting

confidence: 39%

Inductive Ability of Human Developing and Differentiated Dental Mesenchyme

Zheng

Warotayanont

Stahl

et al. 2013

Cells Tissues Organs

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“…For instance, two isoforms of Prx1, called Prx1A and -B, are critical for cartilage, bone, and tooth development (12)(13)(14)(15). Dlx3, -5, and -6 are transcription factors that belong to the distal-less, homeodomain-containing family of transcription factors.…”

mentioning

confidence: 99%

BMP-2 Induces Osterix Expression through Up-regulation of Dlx5 and Its Phosphorylation by p38

Ulsamer

Ortuño

Ruiz

et al. 2008

Journal of Biological Chemistry

193

187

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Osterix, a zinc-finger transcription factor, is specifically expressed in osteoblasts and osteocytes of all developing bones. Because no bone formation occurs in Osterix null mice, Osterix is thought to be an essential regulator of osteoblast differentiation. We report that bone morphogenetic protein-2 (BMP-2) induces an increase in Osterix expression, which is mediated through a homeodomain sequence located in the proximal region of the Osterix promoter. Our results demonstrate that induction of Dlx5 by BMP-2 mediates Osterix transcriptional activation. First, BMP-2 induction of Dlx5 precedes the induction of Osterix. Second, Dlx5 binds to the BMP-responsive homeodomain sequences both in vitro and in vivo. Third, Dlx5 overexpression and knock-down assays demonstrate its role in activating Osterix expression in response to BMP-2. Furthermore, we show that Dlx5 is a novel substrate for p38 MAPK in vitro and in vivo and that Ser-34 and Ser-217 are the sites phosphorylated by p38. Phosphorylation at Ser-34/217 increases the transactivation potential of Dlx5. Thus, we propose that BMP activates expression of Osterix through the induction of Dlx5 and its further transcriptional activation by p38-mediated phosphorylation.Bone is a dynamic tissue that is constantly remodeled throughout life. Bone remodeling activity is dependent on a strict coupling mechanism of osteoclast resorption and new matrix deposition by osteoblasts, and an imbalance between these two activities leads to pathological states such as osteoporosis and osteosclerosis. Commitment to the osteoblast phenotype is ultimately controlled by a specific set of transcription factors activated by signals and regulatory pathways. Among them, bone morphogenetic protein (BMP) 5 signaling has been shown to be involved in bone regeneration and osteoblast differentiation in vitro and in vivo (1-3). BMP target genes include a growing number of tissue-determining transcription factors that promote differentiation of mesenchymal precursors toward the osseous cell phenotypes. For instance, osteogenic induction of bone marrow mesenchymal stem cells or premyogenic C2C12 cells has identified several types of transcription factors such as Id1, several homeodomain proteins, ATF4, the runt homology domain factor Runx2 (Cbfa1) and Osterix (Osx) (for review, see Refs. 4 -6). Runx2 and Osx have been widely accepted as master osteogenic factors since neither Cbfa1 nor Osx null mice form mature osteoblasts (7,8). Nakashima et al. (8) identified Osx as a zinc-finger SP1 family member induced by BMP-2 in C2C12 cells that is specifically expressed in osteoblasts and osteocytes of all developing bones. In Osx-null mice, no bone formation takes place, although Runx2 is expressed, suggesting that Osx acts downstream of Runx2 during bone development (8). It has been suggested that Runx2 would function from the commitment step to the point where osteochondroprogenitors appear, whereas Osx would have a role in the segregation of osteoblasts from osteochondroprogenitors (5). Supporting ...

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“…The two paired‐related homeobox genes, Prx1 and Prx2, are expressed in the mesenchyme of all teeth throughout odontogenesis (Cserjesi et al, 1992; Martin et al, 1995; ten Berge et al, 1998; Lu et al, 1999a; Mitchell et al, 2006). Although Prx1−/− and Prx2−/− mice develop normal teeth (Martin et al, 1995), when both genes are deleted dental abnormalities are observed.…”

Section: Homeobox Genes Involved In the Patterning Of The Dentition Amentioning

confidence: 99%

“…It is however unclear whether this phenotype reflects a direct function of Prx1/2 in mandibular incisor development or an indirect consequence of a shortening of the mandible. More recently, 3D reconstructions of molars from the same mice revealed that the absence of Prx1 and Prx2 results in defects in the morphology of mandibular and maxillary molars (Mitchell et al, 2006).…”

Section: Homeobox Genes Involved In the Patterning Of The Dentition Amentioning

confidence: 99%

Role of homeobox genes in the patterning, specification, and differentiation of ectodermal appendages in mammals

Duverger

Morasso

2008

Journal Cellular Physiology

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Homeobox genes are an evolutionarily conserved class of transcription factors that are key regulators during developmental processes such as regional specification, patterning, and differentiation. In this review, we summarize the expression pattern, loss-and/or gain-of-function mouse models, and naturally occurring mouse and human mutations of known homeobox genes required for the development of ectodermal appendages.

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The Prx1 Homeobox Gene is Critical for Molar Tooth Morphogenesis

Cited by 28 publications

References 29 publications

Inductive Ability of Human Developing and Differentiated Dental Mesenchyme

Inductive Ability of Human Developing and Differentiated Dental Mesenchyme

BMP-2 Induces Osterix Expression through Up-regulation of Dlx5 and Its Phosphorylation by p38

Role of homeobox genes in the patterning, specification, and differentiation of ectodermal appendages in mammals

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