Functional Antagonism between Msx2 and CCAAT/Enhancer-binding Protein α in Regulating the Mouse Amelogenin Gene Expression Is Mediated by Protein-Protein Interaction

Zhou, Yan; Lei, Yaping; Snead, Malcolm L.

doi:10.1074/jbc.m002031200

Cited by 69 publications

(78 citation statements)

References 72 publications

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“…Anomalous tooth development in the Msx2-deficient mice becomes evident at E16.5 when the stellate reticulum and stratum intermedium fail to develop normally resulting in the degeneration of the ameloblast and ultimately the enamel organ. It is postulated that Msx2 participates in the regulation of the spatiotemporal expression of the amelogenin gene during tooth development [124]. In the absence of Msx1, the phenotype of Msx2 mutant mice is greatly amplified.…”

Section: Middle Ear Defects In Msx1-deficient Micementioning

confidence: 99%

Msx homeobox gene family and craniofacial development

2003

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Vertebrate Msx genes are unlinked, homeobox-containing genes that bear homology to the Drosophila muscle segment homeobox gene. These genes are expressed at multiple sites of tissue-tissue interactions during vertebrate embryonic development. Inductive interactions mediated by the Msx genes are essential for normal craniofacial, limb and ectodermal organ morphogenesis, and are also essential to survival in mice, as manifested by the phenotypic abnormalities shown in knockout mice and in humans. This review summarizes studies on the expression, regulation, and functional analysis of Msx genes that bear relevance to craniofacial development in humans and mice.

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Section: Middle Ear Defects In Msx1-deficient Micementioning

confidence: 99%

Msx homeobox gene family and craniofacial development

2003

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“…Msx2 has also been shown to antagonize C/EBP transcription factor in its role of regulating amelogenin gene expression (29). The C/EBP family is important for the regulation of adipogenesis in the early stage especially in the induction of PPAR␥ (30).…”

Section: Msx2 Inhibited Adipocyte Differentiation Of Mesenchymal Cellmentioning

confidence: 99%

Reciprocal Roles of Msx2 in Regulation of Osteoblast and Adipocyte Differentiation

Ichida

Nishimura

Hata

et al. 2004

Journal of Biological Chemistry

176

132

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Mice deficient in the Msx2 gene manifest defects in skull ossification and a marked reduction in bone formation associated with decreases in osteoblast numbers, thus suggesting that Msx2 is involved in bone formation. However, the precise role of Msx2 during osteoblast differentiation is not fully understood. In the present study, we investigated the role of Msx2 in the regulation of osteoblast differentiation in the multipotent mesenchymal cell lines C3H10T1/2 and C2C12 and in murine primary osteoblasts. Introduction of Msx2 induced alkaline phosphatase activity in C3H10T1/2 and C2C12 cells and promoted the calcification of murine primary osteoblasts. This effect of Msx2 was also ob- Differentiation and function of osteoblasts, which play an essential role in bone formation, are regulated by various hormones and cytokines, such as bone morphogenetic proteins (BMPs), 1 fibroblast growth factors, and the Wnt family (1, 2).These factors conduct the transcriptional events that are necessary for the differentiation process of osteoblasts. Runx2/ Cbfa1, an essential transcription factor for bone formation (1, 3), promotes the differentiation of undifferentiated mesenchymal cells into osteoblasts by regulating the transcription of type I collagen, osteopontin, and osteocalcin (4). A more recent study has shown that a zing finger transcription factor, Osterix, is necessary for bone formation and osteoblast differentiation (5). However, the molecular events that regulate the process of osteoblast differentiation have not been fully clarified.Msx2, a homeobox gene, is a mammalian homologue of the Drosophila muscle segment homeobox. Msx2 is known to be induced by BMPs, which play critical roles in bone formation and osteoblast differentiation (2). Msx2-deficient mice develop reduced bone formation, decreases in osteoblasts, impaired chondrogenesis, abnormal calvarial development, and defects in the ectodermal organs including the teeth, hair, and mammary glands (6). In contrast, transgenic mice overexpressing Msx2 show enhanced growth of calvariae (7). Mutations in the MSX2 gene in humans, which affects DNA binding activity, causes defects in skull ossification (8,9). Furthermore an autosomal dominant disorder, Boston-type craniosynostosis, results from a gain-of-function mutation of MSX2 at proline 148 (10, 11). These findings suggest a positive role for Msx2 in bone development and formation. In contrast to these genetic studies, in vitro studies have shown that Msx2 negatively regulates the transcription of the osteoblast-specific genes such as osteocalcin (12, 13). Furthermore Msx2 has been shown to bind to Runx2 and inhibit its transcriptional activity (14). These studies provide the notion that Msx2 serves as a negative regulator for osteoblast differentiation.To understand the complex role of Msx2 in osteoblast differentiation, we examined the effects of Msx2 on osteoblast differentiation of mesenchymal cells. We found that Msx2 promotes the differentiation of mesenchymal cells into the osteoblast lineage in a Runx...

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“…2 has been demonstrated to act as a strong transactivator for amelogenin and to synergize with NF-Y to further increase expression, whereas activation is opposed by Msx2 in a pathway working through protein to protein interactions (1)(2)(3)(4)(5). Mice homozygous for the C/EBP␣ gene deletion die within 8 h of birth from either hypoglycemia (6) or impaired function of type II pneumocytes (7).…”

Section: In Vitro C/ebp␣mentioning

confidence: 99%

CCAAT/Enhancer-binding Protein δ (C/EBPδ) Maintains Amelogenin Expression in the Absence of C/EBPα in Vivo

Zhou

Gonzalez

et al. 2007

Journal of Biological Chemistry

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C/EBP␣ is implicated to regulate mouse amelogenin gene expression during tooth enamel formation in vitro. Because enamel formation occurs during postnatal development and C/EBP␣-deficient mice die at birth, we used the Cre/loxP recombination system to characterize amelogenin expression in C/EBP␣ conditional knock-out mice. Mice carrying the Cre transgene under the control of the human keratin-14 promoter show robust Cre expression in the ameloblast cell lineage. Mating between mice bearing the floxed C/EBP␣ allele with keratin-14-Cre mice generate C/EBP␣ conditional knock-out mice.Real-time PCR analysis shows that removal of one C/⌭〉P␣ allele from the molar enamel epithelial organ of 3-day postnatal mice results in dramatic decrease in endogenous C/⌭〉P␣ mRNA levels and coordinately altered amelogenin mRNA abundance. Conditional deletion of both C/EBP␣ alleles further diminishes C/EBP␣ mRNA levels; however, rather than ablating amelogenin expression, we observe wild-type amelogenin mRNA abundance levels. We examined C/EBP␤ and nuclear factor YA expression, two transcription factors that had previously been shown to modestly participate in amelogenin expression, in vitro but found no significant changes in either of their mRNA abundance levels comparing conditional knock-out mice with wild-type counterparts. Although the abundance of C/EBP␦ is also unchanged in C/EBP␣ conditional knock-out mice, in vitro we find that C/EBP␦ activates the mouse amelogenin promoter and synergistically cooperates with nuclear factor Y, suggesting that C/EBP␦ can functionally substitute for C/EBP␣ to produce an enamel matrix competent to direct biomineralization.

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Functional Antagonism between Msx2 and CCAAT/Enhancer-binding Protein α in Regulating the Mouse Amelogenin Gene Expression Is Mediated by Protein-Protein Interaction

Cited by 69 publications

References 72 publications

Msx homeobox gene family and craniofacial development

Msx homeobox gene family and craniofacial development

Reciprocal Roles of Msx2 in Regulation of Osteoblast and Adipocyte Differentiation

CCAAT/Enhancer-binding Protein δ (C/EBPδ) Maintains Amelogenin Expression in the Absence of C/EBPα in Vivo

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