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The development and growth of the skull is controlled by cranial sutures, which serve as growth centers for osteogenesis by providing a pool of osteoprogenitors. These osteoprogenitors undergo intramembranous ossification by direct differentiation into osteoblasts, which synthesize the components of the extracellular bone matrix. A dysregulation of osteoblast differentiation can lead to premature fusion of sutures, resulting in an abnormal skull shape, a disease called craniosynostosis. Although several genes could be linked to craniosynostosis, the mechanisms regulating cranial suture development remain largely elusive. We have established transgenic mice conditionally expressing an autoactivated platelet-derived growth factor receptor alpha (PDGFRalpha) in neural crest cells (NCCs) and their derivatives. In these mice, premature fusion of NCC-derived sutures occurred at early postnatal stages. In vivo and in vitro experiments demonstrated enhanced proliferation of osteoprogenitors and accelerated ossification of osteoblasts. Furthermore, in osteoblasts expressing the autoactivated receptor, we detected an upregulation of the phospholipase C-gamma (PLC-gamma) pathway. Treatment of differentiating osteoblasts with a PLC-gamma-specific inhibitor prevented the mineralization of synthesized bone matrix. Thus, we show for the first time that PDGFRalpha signaling stimulates osteogenesis of NCC-derived osteoblasts by activating the PLC-gamma pathway, suggesting an involvement of this pathway in the etiology of human craniosynostosis.
Mol Cell Biol 2009 Feb
PMID:Sustained platelet-derived growth factor receptor alpha signaling in osteoblasts results in craniosynostosis by overactivating the phospholipase C-gamma pathway. 1904 72

Fibroblast growth factor receptor 2 (Fgfr2) has two splice variants IIIb and IIIc, which are unique in function and localization. Signalling through Fgfr2IIIb controls epithelial-mesenchymal interactions, which regulate morphogenesis during the development of several organs including the palate and tooth. In this study, we confirm that molar tooth development in Fgfr2IIIb(-/-) mice is arrested early in development and that the molar teeth of Fgf10(-/-) mice develop through all the normal stages of morphogenesis. We show that the molar phenotype of Fgfr2IIIb(-/-) mice is, in part, owing to reduced cell proliferation in both epithelial and mesenchymal compartments. We also show that the developing molar teeth of Fgf10(-/-) mice exhibit reduced cell proliferation. However, this reduction is not sufficient to arrest molar development. Recent evidence has indicated that Fgfr2IIIb/Fgf10 signalling is active in the calvaria in some pathological situations as heterozygous deletion of Fgfr2 exon IIIc in mice leads to ectopic expression of Fgfr2IIIb in the calvarial bones and causes craniosynostosis. Here, we investigate the mRNA expression of Fgfr2IIIb and Fgfr2IIIc as well as their ligands Fgf3, -7 and -10 in the developing murine tooth, palate and calvaria. We show that Fgf7 is expressed in the calvarial mesenchyme adjacent to the developing frontal bone and Fgf10 is expressed by osteoprogenitors in the developing frontal bone condensation. Taken together, we highlight the overlapping roles of Fgfr2IIIb/Fgf10 signalling in controlling epithelial-mesenchymal interactions during normal palate and tooth morphogenesis and how elevated signalling through Fgfr2IIIb/Fgf10 solely within the mesenchyme can result in abnormal calvarial morphogenesis.
J Exp Zool B Mol Dev Evol 2009 Jun 15
PMID:Convergent signalling through Fgfr2 regulates divergent craniofacial morphogenesis. 1920 45

Genetic control of craniofacial morphogenesis requires a complex interaction of numerous genes encoding factors essential for patterning and differentiation. We present two Turkish families with a new autosomal recessive frontofacial dysostosis syndrome characterized by total alopecia, a large skull defect, coronal craniosynostosis, hypertelorism, severely depressed nasal bridge and ridge, bifid nasal tip, hypogonadism, callosal body agenesis and mental retardation. Using homozygosity mapping, we mapped the entity to chromosome 11p11.2-q12.3 and subsequently identified a homozygous c.793C-->T nonsense mutation in the human ortholog of the mouse aristaless-like homeobox 4 (ALX4) gene. This mutation is predicted to result in a premature stop codon (p.R265X) of ALX4 truncating 146 amino acids of the protein including a part of the highly conserved homeodomain and the C-terminal paired tail domain. Although the RNA is stable and not degraded by nonsense-mediated RNA decay, the mutant protein is likely to be non-functional. In a skin biopsy of an affected individual, we observed a hypomorphic interfollicular epidermis with reduced suprabasal layers associated with impaired interfollicular epidermal differentiation. Hair follicle-like structures were present but showed altered differentiation. Our data indicate that ALX4 plays a critical role both in craniofacial development as in skin and hair follicle development in human.
Hum Mol Genet 2009 Nov 15
PMID:ALX4 dysfunction disrupts craniofacial and epidermal development. 1969 47

Dysregulations of osteoblast function induced by gain-of-function genetic mutations in fibroblast growth factor receptors (FGFRs) cause premature fusion of cranial sutures in syndromic craniosynostosis. The pathogenic signaling mechanisms induced by FGFR genetic mutations in human craniosynostosis remain largely unknown. In this study, we have used microarray analysis to investigate the signaling pathways that are activated by FGFR2 mutations in Apert craniosynostosis. Transcriptomic analysis revealed that EGFR and PDGFRalpha expression is abnormally increased in human Apert calvaria osteoblasts compared with wild-type cells. Quantitative RT-PCR and western blot analyses in Apert osteoblasts and immunohistochemical analysis of Apert sutures confirmed the increased EGFR and PDGFRalpha expression in vitro and in vivo. We demonstrate that pharmacological inhibition of EGFR and PDGFR reduces the pathological upregulation of phenotypic osteoblast genes and in vitro matrix mineralization in Apert osteoblasts. Investigation of the underlying molecular mechanisms revealed that activated FGFR2 enhances EGFR and PDGFRalpha mRNA expression via activation of PKCalpha-dependent AP-1 transcriptional activity. We also show that the increased EGFR protein expression in Apert osteoblasts results in part from a post-transcriptional mechanism involving increased Sprouty2-Cbl interaction, leading to Cbl sequestration and reduced EGFR ubiquitination. These data reveal novel molecular crosstalks between activated FGFR2, EGFR and PDGFRalpha that functionally contribute to the osteoblastic dysfunction in Apert craniosynostosis, which may provide a molecular basis for novel therapeutic approaches in this severe skeletal disorder.
Hum Mol Genet 2010 May 01
PMID:Increased EFG- and PDGFalpha-receptor signaling by mutant FGF-receptor 2 contributes to osteoblast dysfunction in Apert craniosynostosis. 2012 86

TSH receptor (TSHR) germline mutations occur as activating mutations in familial non-autoimmune hyperthyroidism (FNAH) or sporadic non-autoimmune hyperthyroidism (SNAH). Up to date 17 constitutively activating TSHR mutations have been reported in 24 families with FNAH. The diagnosis of FNAH should be considered in cases with a positive family history, early onset of hyperthyroidism, goiter, absence of clinical stigmata of autoimmunity and recurrent hyperthyroidism. Moreover, 14 subjects with sporadic non-autoimmune hyperthyroidism and 10 different TSH receptor germline mutations have been reported. The main characteristic of SNAH is a negative family history. Additional consequences of prolonged neonatal hyperthyroidism (mental retardation, speech disturbances and craniosynostosis) have often been reported in SNAH. No genotype-phenotype relationship has been reported in patients with germline TSHR mutations. There is no association of in vitro activities determined by linear regression analysis (LRA) and several clinical indicators of hyperthyroidism activity for SNAH. However, the comparison of the LRA values of sporadic TSHR mutations with LRA values of familial TSHR mutations does show a significantly higher median LRA value for sporadic as compared to familial autosomal dominant hyperthyroidism. This finding is in line with the clinical impression of a more active clinical course in patients with SNAH. However, additional genetic, constitutional or environmental factors are most likely responsible for the phenotypic variations of the disease and the lack of correlation between in vitro activities of the TSHR mutations and the severity of hyperthyroidism.
Mol Cell Endocrinol 2010 Jun 30
PMID:Genetics and phenomics of inherited and sporadic non-autoimmune hyperthyroidism. 2013 63

Gli3 is a zinc-finger transcription factor whose activity is dependent on the level of hedgehog (Hh) ligand. Hh signaling has key roles during endochondral ossification; however, its role in intramembranous ossification is still unclear. In this study, we show that Gli3 performs a dual role in regulating both osteoprogenitor proliferation and osteoblast differentiation during intramembranous ossification. We discovered that Gli3Xt-J/Xt-J mice, which represent a Gli3-null allele, exhibit craniosynostosis of the lambdoid sutures and that this is accompanied by increased osteoprogenitor proliferation and differentiation. These cellular changes are preceded by ectopic expression of the Hh receptor Patched1 and reduced expression of the transcription factor Twist1 in the sutural mesenchyme. Twist1 is known to delay osteogenesis by binding to and inhibiting the transcription factor Runx2. We found that Runx2 expression in the lambdoid suture was altered in a pattern complimentary to that of Twist1. We therefore propose that loss of Gli3 results in a Twist1-, Runx2-dependent expansion of the sutural osteoprogenitor population as well as enhanced osteoblastic differentiation which results in a bony bridge forming between the parietal and interparietal bones. We show that FGF2 will induce Twist1, normalize osteoprogenitor proliferation and differentiation and rescue the lambdoid suture synostosis in Gli3Xt-J/Xt-J mice. Taken together, we define a novel role for Gli3 in osteoblast development; we describe the first mouse model of lambdoid suture craniosynostosis and show how craniosynostosis can be rescued in this model.
Hum Mol Genet 2010 Sep 01
PMID:Gli3Xt-J/Xt-J mice exhibit lambdoid suture craniosynostosis which results from altered osteoprogenitor proliferation and differentiation. 2057 Sep 69

FGFRL1 (fibroblast growth factor receptor like 1) is the most recently discovered member of the FGFR family. It contains three extracellular Ig-like domains similar to the classical FGFRs, but it lacks the protein tyrosine kinase domain and instead contains a short intracellular tail with a peculiar histidine-rich motif. The gene for FGFRL1 is found in all metazoans from sea anemone to mammals. FGFRL1 binds to FGF ligands and heparin with high affinity. It exerts a negative effect on cell proliferation, but a positive effect on cell differentiation. Mice with a targeted deletion of the Fgfrl1 gene die perinatally due to alterations in their diaphragm. These mice also show bilateral kidney agenesis, suggesting an essential role for Fgfrl1 in kidney development. A human patient with a frameshift mutation exhibits craniosynostosis, arguing for an additional role of FGFRL1 during bone formation. FGFRL1 contributes to the complexity of the FGF signaling system.
Cell Mol Life Sci 2011 Mar
PMID:Biology of FGFRL1, the fifth fibroblast growth factor receptor. 2108 29

Apert and Pfeiffer syndromes are hereditary forms of craniosynostosis characterized by midfacial hypoplasia and malformations of the limbs and skull. A serious consequence of midfacial hypoplasia in these syndromes is respiratory compromise due to airway obstruction. In this study, we have evaluated Fgfr1(P250R/+) and Fgfr2(S252W/+) mouse models of these human conditions to study the pathogenesis of midfacial hypoplasia. Our histologic and micro-CT evaluation revealed premature synostosis of the premaxillary-maxillary, nasal-frontal, and maxillary-palatine sutures of the face and dysplasia of the premaxilla, maxilla, and palatine bones. These midfacial abnormalities were detected in the absence of premature ossification of the cranial base at postnatal day 0. Our results indicate that midfacial hypoplasia is not secondary to premature cranial base ossification but rather primary synostosis of facial sutures. Birth Defects Research (Part A), 2011.
Birth Defects Res A Clin Mol Teratol 2011 Jul
PMID:Facial suture synostosis of newborn Fgfr1(P250R/+) and Fgfr2(S252W/+) mouse models of Pfeiffer and Apert syndromes. 2153 17

Retinoic acid receptor responder 2 gene (RARRES2) encodes a novel adipokine protein that plays a crucial role in regulating several biological processes, including immune responses, adipocyte differentiation, type 2 diabetes and metabolic syndrome. In this paper, polymorphisms of the bovine RARRES2 gene were detected in 1300 individuals from six breeds by DNA pooling, CRS-PCR-RFLP and DNA sequencing methods. The results showed that NC_007302:g.117035859A>G, 117035706G>A and 117034290A>G were in the coding region, which resulted in three synonymous mutations and only 117033779C>G was in the 3' UTR. Additionally, associations of the four novel SNPs with growth traits were analyzed in Nanyang cattle up to 2 years of age. In P1-PvuII locus, individuals with genotype BC had greater body height and hucklebone width than those with genotype AA, AC and AB at the age of 24 months. In P3-BamHI locus, individuals with genotype AG had higher hucklebone width than those with genotype GG at the age of 24 months. However, no statistically significant differences were observed in P5-SmaI locus. These results indicated that RARRES2 gene might be a potential candidate gene for marker-assisted selection (MAS).
Mol Biol Rep 2012 Mar
PMID:Exploring polymorphisms of the bovine RARRES2 gene and their associations with growth traits. 2168 71

Methotrexate and aminopterin are folic acid antagonists that inhibit dihydrofolate reductase, resulting in a block in the synthesis of thymidine and inhibition of DNA synthesis. Methotrexate has been used for the treatment of malignancy, rheumatic disorders, and psoriasis and termination of intrauterine pregnancy. Recently, methotrexate has become a standard treatment for ectopic pregnancy. The misdiagnosis of an intrauterine pregnancy as an ectopic pregnancy can result in exposure of a continuing pregnancy to dose levels of methotrexate of 50 mg/m(2) (maternal body surface area). Experimental animal studies have associated methotrexate therapy with embryo death in mice, rats, rabbits, and monkeys. Structural malformations have been most consistently produced in rabbits at a maternal dose level of 19.2 mg/kg. Abnormalities in rabbits include hydrocephalus, microphthalmia, cleft lip and palate, micrognathia, dysplastic sacral and caudal vertebrate, phocomelia, hemimelia, syndactyly, and ectrodactyly. Based on human case reports of methotrexate exposure during pregnancy, a methotrexate embryopathy has been described that includes growth deficiency, microcephaly, hypoplasia of skull bones, wide fontanels, coronal or lambdoidal craniosynostosis, upswept frontal scalp hair, broad nasal bridge, shallow supraorbital ridges, prominent eyes, low-set ears, maxillary hypoplasia, epicanthal folds, short limbs, talipes, hypodactyly, and syndactyly. This syndrome may be associated with exposures between 6 and 8 weeks after conception and dose levels of 10 mg/week or greater. More recent case reports of methotrexate exposure for the misdiagnosis of ectopic pregnancy involve treatment before 6 weeks after conception and have raised the suggestion of a distinct syndrome due to such early exposures. Tetralogy of Fallot and perhaps other neural crest cell-related abnormalities may be features of this early syndrome. A disproportionality analysis of methotrexate and aminopterin case reports and series provides support for pulmonary atresia, craniosynostosis, and limb deficiencies as reported more often than expected in methotrexate-exposed children. Denominator-based data will be welcome to better define elements of a methotrexate embryopathy and possibly to distinguish an early exposure syndrome from anomalies traditionally associated with methotrexate exposure.
Birth Defects Res A Clin Mol Teratol 2012 Apr
PMID:Teratogen update: methotrexate. 2243 86


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