Abnormalities in cartilage and bone development in the Apert syndrome FGFR2+/S252W mouse

Wang, Yingli; Xiao, Ran; Yang, Fan; Karim, Baktiar O.; Iacovelli, Anthony J.; Cai, Juanliang; Lerner, Charles P.; Richtsmeier, Joan T.; Leszl, Jen M.; Hill, Cheryl A.; Yu, Kai; Ornitz, David M.; Elisseeff, Jennifer H.; Huso, David L.; Jabs, Ethylin Wang

doi:10.1242/dev.01914

Cited by 174 publications

(280 citation statements)

References 41 publications

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“…However, a group of genes involved in cardiac development (Gata4 (Kuo et al 1997, Tevosian et al 2002, Adam19 (Kurohara et al 2004), Fgf4, and Fgfr2 (Feldman et al 1995, Wang et al 2005, and Bmp4 (Liu et al 2004, Zakin & De Robertis 2004 are down- Effect of IVF on mouse preimplantation embryo regulated, and Cebpa knock outs show abnormalities in adipogenesis, hematopoiesis, hepatic, and lung morphology and premature death (Flodby et al 1996, Zhang et al 2004. It is possible that these changes are temporary and disappear, but could persist and affect long term development, extending the Barker hypothesis (Barker 1998) to the preimplantation period.…”

Section: Discussionmentioning

confidence: 99%

Effect of in vitro fertilization on gene expression and development of mouse preimplantation embryos

Giritharan¹,

Talbi²,

Donjacour³

et al. 2007

Reproduction

144

127

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In vitro culture (IVC) of preimplantation mouse embryos is associated with changes in gene expression. It is however, not known if the method of fertilization affects the global pattern of gene expression. We compared gene expression and development of mouse blastocysts produced by in vitro fertilization (IVF) versus blastocysts fertilized in vivo and cultured in vitro from the zygote stage (IVC) versus control blastocysts flushed out of the uterus on post coital day 3.5. The global pattern of gene expression was assessed using the Affymetrix 430 2.0 chip. It appears that each method of fertilization has a unique pattern of gene expression and development. Embryos cultured in vitro had a reduction in the number of trophoblastic cells (IVF 33.5 cells, IVC 39.9 cells, and 49.6 cells in the in vivo group) and, to a lesser degree, of inner cell mass cells (12.8, 11.7, and 13.8 respectively). The inner cell mass nuclei were larger after culture in vitro (140 mm 2 , 113 mm 2 , and 86 mm 2 respectively). Although a high number of genes (1912) was statistically different in the IVF cohort when compared with the in vivo control embryos, the magnitude of the changes in gene expression were low and only a minority of genes (29 genes) was changed more than fourfold. Surprisingly, IVF embryos were different from IVC embryos (3058 genes were statistically different, but only three changed more than fourfold). Proliferation, apoptosis, and morphogenetic pathways are the most common pathways altered after IVC. Overall, IVF and embryo culture have a profound effect on gene expression pattern and phenotype of mouse preimplantation embryos.

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Section: Discussionmentioning

confidence: 99%

Effect of in vitro fertilization on gene expression and development of mouse preimplantation embryos

Giritharan¹,

Talbi²,

Donjacour³

et al. 2007

Reproduction

144

127

View full text Add to dashboard Cite

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“…Mutations in both FGFR1 and -2 have been implicated in craniofacial syndromes, but are more commonly found in craniosynostosis, premature fusion of sutures due to disrupted intramembranous bone growth (reviewed in Chen and Deng, 2005). Although an in vivo role for Stats downstream of FGFR2 has not yet been shown, mouse models of craniosynostosis containing altered FGFR2, display several phenotypes that overlap with those observed in FKO, Wnt1-Cre; Floxdel/KI, or Tcfap2a ϩ/Ϫ mice including shortened snouts, dental malocclusion, widespaced eyes, and cleft palate (Zhang et al, 1996;Nottoli et al, 1998;De Moerlooze et al, 2000;Hajihosseini et al, 2001;Eswarakumar et al, 2002Eswarakumar et al, , 2004Chen et al, 2003;Brewer et al, 2004;Nelson and Williams, 2004;Wang et al, 2005). Thus, the presence of a STAT site in the FNP/LBM-specific enhancer likely places AP-2␣ downstream of FGFR signaling in the FNP, which is consistent with other studies showing FGF-dependent changes of Tcfap2a in the craniofacial region (Shen et al, 1997;Cordero et al, 2004).…”

Section: Stat Proteins Act Upstream Of Tcfap2amentioning

confidence: 99%

Frontal nasal prominence expression driven by Tcfap2a relies on a conserved binding site for STAT proteins

Donner

Williams

2006

Developmental Dynamics

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The AP-2 transcription factor family is linked with development of the head and limbs in both vertebrate and invertebrate species. Recent evidence has also implicated this gene family in the evolution of the neural crest in chordates, a critical step that allowed the development and elaboration of the vertebrate craniofacial skeleton. In mice, the inappropriate embryonic expression of one particular AP-2 gene, Tcfap2a, encoding AP-2␣, results in multiple developmental abnormalities, including craniofacial and limb defects. Thus, Tcfap2a provides a valuable genetic resource to analyze the regulatory hierarchy responsible for the evolution and development of the face and limbs. Previous studies have identified a 2-kilobase intronic region of both the mouse and human AP-2␣ locus that directs expression of a linked LacZ transgene to the facial processes and the distal mesenchyme of the limb bud in transgenic mice. Further analysis identified two highly conserved regions of ϳ200 -400 bp within this tissue-specific enhancer. We have now initiated a transgenic and biochemical analysis of the most important of these highly conserved regions. Our analysis indicates that although the sequences regulating face and limb expression have been integrated into a single enhancer, different cis-acting sequences ultimately control these two expression domains. Moreover, these studies demonstrate that a conserved STAT binding site provides a major contribution to the expression of Tcfap2a in the facial prominences. Developmental Dynamics 235: 1358 -1370, 2006.

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“…Mutations in FGFR2 and FGFR3 can also alter ligand specificity (21,22); such gain-of-function mutations have been found in patients with the congenital craniofacial malformation disorders, Apert and Crouzon syndromes, characterized by craniosynostosis and syndactyly of hands and feet (23,24). Moreover, these mutations are directly correlated with development of Apert syndrome in mouse models (25)(26)(27).In a search for novel druggable therapeutic targets, we have undertaken sequencing of tyrosine kinase genes in a variety of tumor types. Endometrial cancer, the most common gynecological cancer in industrialized countries, with no curative treatment for patients with nonresectable disease (28), was examined in early discovery experiments.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Drug-sensitiveFGFR2mutations in endometrial carcinoma

Dutt

Salvesen

Chen

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

326

283

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Oncogenic activation of tyrosine kinases is a common mechanism of carcinogenesis and, given the druggable nature of these enzymes, an attractive target for anticancer therapy. Here, we show that somatic mutations of the fibroblast growth factor receptor 2 (FGFR2) tyrosine kinase gene, FGFR2, are present in 12% of endometrial carcinomas, with additional instances found in lung squamous cell carcinoma and cervical carcinoma. These FGFR2 mutations, many of which are identical to mutations associated with congenital craniofacial developmental disorders, are constitutively activated and oncogenic when ectopically expressed in NIH 3T3 cells. Inhibition of FGFR2 kinase activity in endometrial carcinoma cell lines bearing such FGFR2 mutations inhibits transformation and survival, implicating FGFR2 as a novel therapeutic target in endometrial carcinoma.endometrial cancer ͉ fibroblast growth factor receptor 2 ͉ oncogene ͉ targeted therapy ͉ tyrosine kinase T yrosine kinases play a major role in transduction of proliferative signals and can become oncogenic when deregulated by somatic mutation (1). Somatically altered tyrosine kinases have proven to be tractable therapeutic targets in several tumor types; examples of successfully targeted tyrosine kinases include ABL1 in chronic myeloid leukemia (2), KIT in gastrointestinal stromal tumors (3), ERBB2 in breast cancer (4), and EGFR in non-small-cell lung cancer (5-7). The tyrosine kinase family has not been exhaustively studied in human cancer, and it is likely that additional tyrosine kinase therapeutic targets remain to be discovered.The fibroblast growth factor receptor (FGFR) tyrosine kinase family, which is comprised of four kinases that differentially respond to 18 FGF ligands (8, 9), has long been implicated in cancer. Translocations involving FGFR3, and activating somatic mutations in FGFR3, have been identified in multiple myeloma patients (10, 11), and translocations of FGFR1 have been found in patients with 8p11 myeloproliferative syndrome (12). Isolated cases of a missense mutation of FGFR4 in a lung adenocarcinoma patient and missense mutations of FGFR2 in a lung squamous cell carcinoma patient and gastric cancer patient have also been reported (13,14). In addition to these documented examples of somatic mutation of FGFR family members in cancer, a germ-line polymorphism in the second intron of FGFR2 was found to be associated with breast cancer in genomewide association studies (15,16).FGFR1-FGFR3 are characterized by alternative splicing of the mRNA encoding the third Ig-like repeat in the extracellular ligand-binding domain. This differential splicing determines ligand specificity such that isoforms expressed primarily in epithelial cells (IIIb) preferentially bind FGF ligands expressed by mesenchymal cells, and isoforms expressed primarily in mesenchymal cells (IIIc) preferentially bind FGF ligands expressed by epithelial cells (17)(18)(19). Alteration of this restricted expression pattern can lead to oncogenic transformation (20). Mutations in FGFR2 and FGF...

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Abnormalities in cartilage and bone development in the Apert syndrome FGFR2+/S252W mouse

Abstract: SummaryAbnormalities in cartilage and bone development in the Apert syndrome FGFR2 +/S252W

Cited by 174 publications

References 41 publications

Effect of in vitro fertilization on gene expression and development of mouse preimplantation embryos

Effect of in vitro fertilization on gene expression and development of mouse preimplantation embryos

Frontal nasal prominence expression driven by Tcfap2a relies on a conserved binding site for STAT proteins

Drug-sensitiveFGFR2mutations in endometrial carcinoma

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