Perinatal Lethality and Multiple Craniofacial Malformations in MSX2 Transgenic Mice

Winograd, Jonathan M.; Reilly, Michael P.; Roe, Rick; Lutz, Janita; Laughner, Erik; Xu, Xiaoqiang; Hu, Ling; Asakura, Toshio; Kolk, Craig Vander; Strandberg, John D.; Semenza, Gregg L.

doi:10.1093/hmg/6.3.369

Cited by 105 publications

(59 citation statements)

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“…39 Thus, it is possible that the inability of the apoptotic neural cells to migrate, may have contributed to acrania in this model, as seen in other models. 19,[40][41][42] Specifically, Msx2 transgenic mice display increased death of CNC cells, resulting in a cell number deficiency in branchial arches associated with craniofacial morphogenesis. 41 Interestingly, Msx2 induces apoptosis in CNC cells of rhombomeres 3 and 5, 43 but increases proliferation of osteoblasts in the osteogenic front of postnatal mice, 44 leading to exencephaly-like NTDs.…”

Section: Discussionmentioning

confidence: 99%

“…19,[40][41][42] Specifically, Msx2 transgenic mice display increased death of CNC cells, resulting in a cell number deficiency in branchial arches associated with craniofacial morphogenesis. 41 Interestingly, Msx2 induces apoptosis in CNC cells of rhombomeres 3 and 5, 43 but increases proliferation of osteoblasts in the osteogenic front of postnatal mice, 44 leading to exencephaly-like NTDs. This observation is recapitulated in Tcof1 heterozygous mice and Tulp3 transgenic mice, which display increased neuroepithelial apoptosis during development, exencephaly, and premature death.…”

Section: Discussionmentioning

confidence: 99%

“…The data suggest that the mechanism of Nell-1 overexpression-induced acrania may be the coordinated induction of apoptosis in several cell types, a finding also reported in Msx2 transgenic mice. 41 Nell-1 has been previously reported to signal through the PKC pathway, 25 which is known to induce apoptosis in osteoblasts. 45 In fact, in other systems, PKC activation has also induced FasL gene transcription.…”

Section: Discussionmentioning

confidence: 99%

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Nell-1 induces acrania-like cranioskeletal deformities during mouse embryonic development

Zhang

Cowan

Jiang

et al. 2006

Laboratory Investigation

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We previously reported NELL-1 as a novel molecule overexpressed during premature cranial suture closure in patients with craniosynostosis (CS). Nell-1 overexpression also results in premature suture closure/ craniosynostosis in newborn transgenic mice. On a cellular level, increased levels of Nell-1 induce osteoblast differentiation and apoptosis. In this report, mice over-expressing Nell-1 were examined during embryonic development as well as shortly after birth for further analysis of craniofacial defects including neural tube defects (NTDs). The results demonstrated that overexpression of Nell-1 could induce acrania at relatively late gestation stage (E15.5) in mouse embryos, through massive apoptosis in calvarial osteoblasts and neural cells. The induced apoptosis was associated with an increase in Fas and Fas-L production. In addition, transgenic E15.5 and newborn transgenic mice with the CS phenotype displayed distortion of the chondrocranium associated with premature hypertrophy and increased apoptosis of chondrocytes. These findings were also verified in vitro with primary chondrocytes transduced with AdNell-1. In conclusion, Nell-1 overexpression can induce craniofacial anomalies associated with neural tube defects during embryonic development and may involve mechanisms of massive apoptosis associated with the Fas/Fas-L signaling pathway. NELL-1: used when describing the human gene; NELL-1: used when describing the human protein; Nell-1: used when describing the rodent gene; Nell-1: used when describing the rodent protein Laboratory Investigation (2006) 86, 633-644.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Nell-1 induces acrania-like cranioskeletal deformities during mouse embryonic development

Zhang

Cowan

Jiang

et al. 2006

Laboratory Investigation

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“…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.…”

mentioning

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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“…The ski-null mice show defects in cranial neural tube closure leading to exencephaly and a marked decrease in skeletal muscle mass [93]. The ability of Ski to regulate craniofacial development may be related to its antagonizing effect on BMP signaling as facial clefting and exencephaly have been also observed in transgenic mice overexpressing the BMP target gene Msx2 [94]. Thus, it seems that the function of Ski in development is via antagonizing BMP signaling while its role in promoting oncogenic transformation is mainly through regulating TGF-β signaling.…”

Section: Modulation Of Downstream Tran-scription Mediatorsmentioning

confidence: 99%

Negative regulation of TGF-β signaling in development

Chen

Meng

2004

Cell Res

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The TGF-β superfamily members have important roles in controlling patterning and tissue formation in both invertebrates and vertebrates. Two types of signal transducers, receptors and Smads, mediate the signaling to regulate expression of their target genes. Despite of the relatively simple signal transduction pathway, many modulators have been found to contribute to a tight regulation of this pathway in a variety of mechanisms. This article reviews the negative regulation of TGF-β signaling with focus on its roles in vertebrate development.

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Perinatal Lethality and Multiple Craniofacial Malformations in MSX2 Transgenic Mice

Cited by 105 publications

References 49 publications

Nell-1 induces acrania-like cranioskeletal deformities during mouse embryonic development

Nell-1 induces acrania-like cranioskeletal deformities during mouse embryonic development

Reciprocal Roles of Msx2 in Regulation of Osteoblast and Adipocyte Differentiation

Negative regulation of TGF-β signaling in development

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