Tissue‐specific responses to aberrant FGF signaling in complex head phenotypes

COVER PHOTOGRAPH: Multimodal imaging and segmentation used to visualize skull (yellow), brain (pink), inner ear (green), nasopharynx (green) and globe of the eye (blue) in Fgfr2c^C342Y/+Crouzon syndrome mice (top) and normal littermates (bottom). From Martínez‐Abadías et al., Developmental Dynamics 242:80–94, 2013.     

Beyond the closed suture in apert syndrome mouse models: Evidence of primary effects of FGFR2 signaling on facial shape at birth

Apert syndrome is a congenital disorder caused mainly by two neighboring mutations on fibroblast growth factor receptor 2 (FGFR2). Premature closure of the coronal suture is commonly considered the identifying and primary defect triggering or preceding the additional cranial malformations of Apert phenotype. Here we use two transgenic mouse models of Apert syndrome, Fgfr2^+/S252W and Fgfr2^+/P253R, to explore variation in cranial phenotypes in newborn (P0) mice. Results show that the facial skeleton is the most affected region of the cranium. Coronal suture patency shows marked variation that is not strongly correlated with skull dysmorphology. The craniofacial effects of the FGFR2 mutations are similar, but Fgfr2^+/S252W mutant mice display significantly more severe dysmorphology localized to the posterior palate. Our results demonstrate that coronal suture closure is neither the primary nor the sole locus of skull dysmorphology in these mouse models for Apert syndrome, but that the face is also primarily affected. Developmental Dynamics 239:3058–3071, 2010. © 2010 Wiley‐Liss, Inc.     

Postnatal brain and skull growth in an Apert syndrome mouse model

Craniofacial and neural tissues develop in concert throughout prenatal and postnatal growth. FGFR‐related craniosynostosis syndromes, such as Apert syndrome (AS), are associated with specific phenotypes involving both the skull and the brain. We analyzed the effects of the FGFR P253R mutation for AS using the Fgfr2^+/P253R Apert syndrome mouse to evaluate the effects of this mutation on these two tissues over the course of development from day of birth (P0) to postnatal day 2 (P2). Three‐dimensional magnetic resonance microscopy and computed tomography images were acquired from Fgfr2^+/P253R mice and unaffected littermates at P0 (N = 28) and P2 (N = 20).Three‐dimensional coordinate data for 23 skull and 15 brain landmarks were statistically compared between groups. Results demonstrate that the Fgfr2^+/P253R mice show reduced growth in the facial skeleton and the cerebrum, while the height and width of the neurocranium and caudal regions of the brain show increased growth relative to unaffected littermates. This localized correspondence of differential growth patterns in skull and brain point to their continued interaction through development and suggest that both tissues display divergent postnatal growth patterns relative to unaffected littermates. However, the change in the skull–brain relationship from P0 to P2 implies that each tissue affected by the mutation retains a degree of independence, rather than one tissue directing the development of the other. © 2013 Wiley Periodicals, Inc.     

The missense mutation W290R in Fgfr2 causes developmental defects from aberrant IIIb and IIIc signaling

Missense mutations in the Fibroblast Growth Factor Receptor 2 (FGFR2) have been identified in human craniosynostotic syndromes such as Crouzon (CS) and Pfeiffer (PS). FGFR2 has two major isoforms, IIIb and IIIc, generated through alternative splicing with their own temporal, spatial, and ligand‐binding specificities. In this study, we report the identification and characterization of a missense mutation in codon 290 of murine Fgfr2 (W290R). The defects in W290R mutants are suggestive of disruption of signalling in both IIIb and IIIc isoforms of the Fgfr2 gene. Heterozygous mutants presented with features resembling those found in patients with CS. Fgfr2^W290R homozygotes displayed constitutive FGFR2 activation with increased, but correct tissue‐specific, expression of the IIIb and IIIc isoforms in many of the defective organs. Our Fgfr2^W290R mouse model thus represents an excellent mouse model of CS to probe the many questions around the pathogenesis of craniosynostotic birth defects consequent to defects in FGF signaling. Developmental Dynamics 239:1888–1900, 2010. © 2010 Wiley‐Liss, Inc.     

Oligodendroglial fibroblast growth factor receptor 1 gene targeting protects mice from experimental autoimmune encephalomyelitis through ERK/AKT phosphorylation

Fibroblast growth factors (FGFs) exert diverse biological effects by binding and activation of specific fibroblast growth factor receptors (FGFRs). FGFs and FGFRs have been implicated in demyelinating pathologies including multiple sclerosis. In vitro activation of the FGF2/FGFR1 pathway results in downregulation of myelin proteins. FGF1, 2 and 9 have been shown to be involved in the pathology of multiple sclerosis. Recent studies on the function of oligodendroglial FGFR1 in a model of toxic demyelination showed that deletion of FGFR1 led to increased remyelination and preservation of axonal density and an increased number of mature oligodendrocytes. In the present study the in vivo function of oligodendroglial FGFR1 was characterized using an oligodendrocyte‐specific genetic approach in the most frequently used model of multiple sclerosis the MOG_35‐55‐induced EAE. Oligodendroglial FGFR1 deficient mice (referred to as Fgfr1^ind−/−) showed a significantly ameliorated disease course in MOG_35‐55‐induced EAE. Less myelin and axonal loss, and reduced lymphocyte and macrophage/microglia infiltration were found in Fgfr1^ind−/− mice. The reduction in disease severity in Fgfr1^ind−/− mice was accompanied by ERK/AKT phosphorylation, and increased expression of BDNF and TrkB. Reduced proinflammatory cytokine and chemokine expression was seen in Fgfr1^ind−/− mice compared with control mice. Considering that FGFR inhibitors are used in cancer trials, the oligodendroglial FGFR1 pathway may provide a new target for therapy in multiple sclerosis.     

Soluble form of FGFR2 with S252W partially prevents craniosynostosis of the apert mouse model

Background: Apert syndrome (AS) is characterized by craniosynostosis, midfacial hypoplasia, and bony syndactyly. It is an autosomal dominantly inherited disease caused by point mutations (S252W or P253R) in fibroblast growth factor receptor (FGFR) 2. These mutations cause activation of FGFR2 depending on ligand binding. Recently, an AS mouse model, Fgfr2^+/S252W, showed phenotypes similar to those of AS patients. We previously reported that the soluble form of FGFR2^S252W (sFGFR2IIIc^S252W) efficiently inhibits enhanced osteoblastic differentiation caused by FGFR2 activation in AS in vitro, presumably because FGFs binding to FGFRs is interrupted. In this study, we developed Fgfr2^+/S252W (Ap) mice expressing the sFGFR2IIIc^S252W protein, and we investigated the effects of sFGFR2IIIc^S252W on AS‐like phenotypes. Results: In Ap mice, the coronal suture (CS) was fused prematurely at P1. In addition, the mice exhibited a widened interfrontal suture (IFS) with ectopic bone and thickened cartilage formation. In Fgfr2^+/S252W sFGFR2IIIc^S252W (Ap/Sol) mice, the CS was similar to that of wild‐type mice. Ap/Sol mice did not show any ectopic bone or cartilage formation in the IFS, but showed a wider IFS than that of the wild‐type mice. Conclusions: sFGFR2IIIc^S252W may partially prevent craniosynostosis in the Apert mouse model by affecting the CS and IFS in vivo. Developmental Dynamics 243:560–567, 2014. © 2013 The Authors Developmental Dynamics published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists.     

Brain phenotypes in two FGFR2 mouse models for Apert syndrome

Apert syndrome (AS) is one of at least nine disorders considered members of the fibroblast growth factor receptor (FGFR) ‐1, ‐2, and ‐3–related craniosynostosis syndromes. Nearly 100% of individuals diagnosed with AS carry one of two neighboring mutations on Fgfr2. The cranial phenotype associated with these two mutations includes coronal suture synostosis, either unilateral (unicoronal synostosis) or bilateral (bicoronal synostosis). Brain dysmorphology associated with AS is thought to be secondary to cranial vault or base alterations, but the variation in brain phenotypes within Apert syndrome is unexplained. Here, we present novel three‐dimensional data on brain phenotypes of inbred mice at postnatal day 0 each carrying one of the two Fgfr2 mutations associated with AS. Our data suggest that the brain is primarily affected, rather than secondarily responding to skull dysmorphogenesis. Our hypothesis is that the skull and brain are both primarily affected in craniosynostosis and that shared phenogenetic developmental processes affect both tissues in craniosynostosis of Apert syndrome. Developmental Dynamics 239:987–997, 2010. © 2010 Wiley‐Liss, Inc.     

Genetic rescue of Muenke syndrome model hearing loss reveals prolonged FGF-dependent plasticity in cochlear supporting cell fates

The stereotyped arrangement of cochlear sensory and supporting cells is critical for auditory function. Our previous studies showed that Muenke syndrome model mice (Fgfr3^P244R/+) have hearing loss associated with a supporting cell fate transformation of two Deiters'' cells to two pillar cells. We investigated the developmental origins of this transformation and found that two prospective Deiters'' cells switch to an outer pillar cell-like fate sequentially between embryonic day 17.5 (E17.5) and postnatal day 3 (P3). Unexpectedly, the Fgfr3^P244R/+ hearing loss and supporting cell fate transformation are not rescued by genetically reducing fibroblast growth factor 8 (FGF8), the FGF receptor 3c (FGFR3c) ligand required for pillar cell differentiation. Rather, reducing FGF10, which normally activates FGFR2b or FGFR1b, is sufficient for rescue of cochlear form and function. Accordingly, we found that the P244R mutation changes the specificity of FGFR3b and FGFR3c such that both acquire responsiveness to FGF10. Moreover, Fgf10 heterozygosity does not block the Fgfr3^P244R/+ supporting cell fate transformation but instead allows a gradual reversion of fate-switched cells toward the normal phenotype between P5 and at least P14. This study indicates that Deiters'' and pillar cells can reversibly switch fates in an FGF-dependent manner over a prolonged period of time. This property might be exploited for the regulation of sensory cell regeneration from support cells.     

Predicting calvarial growth in normal and craniosynostotic mice using a computational approach

During postnatal calvarial growth the brain grows gradually and the overlying bones and sutures accommodate that growth until the later juvenile stages. The whole process is coordinated through a complex series of biological, chemical and perhaps mechanical signals between various elements of the craniofacial system. The aim of this study was to investigate to what extent a computational model can accurately predict the calvarial growth in wild‐type (WT) and mutant type (MT) Fgfr2^C342Y/+ mice displaying bicoronal suture fusion. A series of morphological studies were carried out to quantify the calvarial growth at P3, P10 and P20 in both mouse types. MicroCT images of a P3 specimen were used to develop a finite element model of skull growth to predict the calvarial shape of WT and MT mice at P10. Sensitivity tests were performed and the results compared with ex vivo P10 data. Although the models were sensitive to the choice of input parameters, they predicted the overall skull growth in the WT and MT mice. The models also captured the difference between the ex vivoWT and MT mice. This modelling approach has the potential to be translated to human skull growth and to enhance our understanding of the different reconstruction methods used to manage clinically the different forms of craniosynostosis, and in the long term possibly reduce the number of re‐operations in children displaying this condition and thereby enhance their quality of life.     

Novel FGFR2 mutations in Crouzon and Jackson-Weiss syndromes show allelic heterogeneity and phenotypic variability

Mutations have been reported for several craniosynostotic disordersin exon Illa (exon U or 7) or Illc (exon B or 9) of the fibroblastgrowth factor receptor 2 gene (FGFR2). Among the conditionswith FGFR2 mutations are two autosomal dominant syndromes, Crouzonand Jackson–Weiss. In this study, 24 Crouzon and one Jackson–Weisssyndrome patients were screened for mutations in the two exonsby direct sequencing, and mutations were detected in 28% (7/25)of all cases. Five different mutations were found includingtwo novel (W290G, C342W) and two previously reported, recurrentmutations for Crouzon syndrome (A344A, S354C), and one new mutationfor Jackson-Weiss syndrome (C342R). The W290G mutation was foundin exon Illa which is common to both alternatively spliced formsof FGFR2, BEK (expressed predominantly in primordial bones)and KGFR (expressed preferentially in epithelia). Atypical Crouzonsyndrome features of epithelial-derived anal and/or externalear anomalies were present in the two affected family memberswith the mutation. This phenotype possibly reflects the expressionof both mutant BEK and KGFR. In addition, the Jackson-Weisssyndrome mutation, C342R, in exon Illc was observed previouslyin other craniosynostotic syndromes, Crouzon and Pfeiffer. Theseresults underscore the allelic heterogeneity of these conditionsand the complexity of the phenotypic consequences of FGFR2 mutations.     

Conditional gene inactivation reveals roles for Fgf10 and Fgfr2 in establishing a normal pattern of epithelial branching in the mouse lung

Fibroblast growth factor 10 (FGF10) signaling through FGF receptor 2 (FGFR2) is required for lung initiation. While studies indicate that Fgf10 and Fgfr2 are also important at later stages of lung development, their roles in early branching events remain unclear. We addressed this question through conditional inactivation of both genes in mouse subsequent to lung initiation. Inactivation of Fgf10 in lung mesenchyme resulted in smaller lobes with a reduced number of branches. Inactivation of Fgfr2 in lung epithelium resulted in disruption of lobes and small epithelial outgrowths that arose arbitrarily along the main bronchi. In both mutants, there was an increase in cell death. Also, the expression patterns of key signaling molecules implicated in branching morphogenesis were altered and a proximal lung marker was expanded distally. Our results indicate that both Fgf10 and Fgfr2 are required for a normal branching program and for proper proximal–distal patterning of the lung.Developmental Dynamics 238:1999–2013, 2009. © 2009 Wiley‐Liss, Inc.     

Fibroblast growth factor receptor 3 activation plays a causative role in urothelial cancer pathogenesis in cooperation with Pten loss in mice

Although somatic mutations and overexpression of the tyrosine kinase fibroblast growth factor receptor 3 (FGFR3) are strongly associated with bladder cancer, evidence for their functional involvement in the pathogenesis remains elusive. Previously we showed that activation of Fgfr3 alone is not sufficient to initiate urothelial tumourigenesis in mice. Here we hypothesize that cooperating mutations are required for Fgfr3‐dependent tumourigenesis in the urothelium and analyse a mouse model in which an inhibitor of Pi3k–Akt signalling, Pten, is deleted in concert with Fgfr3 activation (UroIICreFgfr3^+/K644EPten^flox/flox). Two main phenotypical characteristics were observed in the urothelium: increased urothelial thickness and abnormal cellular histopathology, including vacuolization, condensed cellular appearance, enlargement of cells and nuclei, and loss of polarity. These changes were not observed when either mutation was present individually. Expression patterns of known urothelial proteins indicated the abnormal cellular differentiation. Furthermore, quantitative analysis showed that Fgfr3 and Pten mutations cooperatively caused cellular enlargement, while Pten contributed to increased cell proliferation. Finally, FGFR3 overexpression was analysed along the level of phosphorylated mTOR in 66 T1 urothelial tumours in tissue microarray, which supported the occurrence of functional association of these two signalling pathways in urothelial pathogenesis. Taken together, this study provides evidence supporting a functional role of FGFR3 in the process of pathogenesis in urothelial neoplasms. Given the wide availability of inhibitors specific to FGF signalling pathways, our model may open the avenue for FGFR3‐targeted translation in urothelial disease. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Basic fibroblast growth factor: effects on matrix remodeling, receptor expression, and transduction pathway in human periosteal fibroblasts with FGFR2 gene mutation.

The Crouzon syndrome, which is associated with fibroblast growth factor receptor (FGFR2) mutations, is characterized by premature fusion of cranial sutures. We used an in vitro model of cultured periosteal fibroblasts from normal subjects and from Crouzon patients with FGFR2 mutation. We analyzed the matrix turnover rate and the effects of adding FGF2 by evaluating fibronectin synthesis and the activity of some proteolytic enzymes. To assess the role of some FGF signaling molecules involved in FGFR2 regulation, we studied Grb2 tyrosine phosphorylation and the phosphotyrosine proteins associated with Grb2. The iodinate FGF binding assay was performed to quantify FGFR expression. Compared with normal fibroblasts, fibronectin synthesis was decreased in Crouzon fibroblasts, and protease activities in cells and medium were enhanced, suggesting that excess fibronectin catabolism is present. Differences were more marked when FGF2 was added. Very few phosphoproteins were visible in anti-Grb2 immunoprecipitations from Crouzon fibroblasts, which showed a significant increase in the number of high-affinity and low-affinity FGF2 receptors. These results suggest that the abnormal genotype and the Crouzon cellular phenotype are related. To compensate the low levels of tyrosine phosphorylation, Crouzon cells might increase the numbers of FGFR2, thus increasing the cell surface binding sites for FGF2.     

Kallmann syndrome: fibroblast growth factor signaling insufficiency?

Kallmann syndrome (KAL) is a developmental disease that combines hypogonadotropic hypogonadism and anosmia. Anosmia is related to the absence or hypoplasia of the olfactory bulbs. Hypogonadism is due to GnRH deficiency and is likely to result from the failed embryonic migration of GnRH-synthesizing neurons. These cells normally migrate from the olfactory epithelium to the forebrain along the olfactory nerve pathway. KAL is phenotypically and genetically heterogeneous. The gene responsible for the X-chromosome linked form of the disease (KAL1) has been identified in 1991. KAL1 encodes anosmin-1, an approx. 95-kDa glycoprotein of unknown function which is present locally in various extracellular matrices during the period of organogenesis. The recent finding that FGFR1 mutations are involved in an autosomal dominant form of Kallmann syndrome (KAL2), combined with the analysis of mutant mouse embryos that no longer express Fgfr1 in the telencephalon, suggests that the disease results from a deficiency in FGF signaling at the earliest stage of olfactory bulb morphogenesis. We propose that the role of anosmin-1 is to enhance FGF signaling and suggest that the gender difference in anosmin-1 dose (because KAL1 partially escapes X-inactivation) explains the higher prevalence of the disease in males.     

Mosaic analysis of cell rearrangements during ureteric bud branching in dissociated/reaggregated kidney cultures and in vivo

Background : Cell rearrangements mediated by GDNF/Ret signaling underlie the formation of the ureteric bud (UB) tip domain during kidney development. Whether FGF signaling also influences these rearrangements is unknown. Chimeric embryos are a powerful tool for examining the genetic controls of cellular behaviors, but generating chimeras by traditional methods is expensive and laborious. Dissociated fetal kidney cells can reorganize to form complex structures including branching UB tubules, providing an easier method to generate renal chimeras. Results : Cell behaviors in normal or chimeric kidney cultures were investigated using time‐lapse imaging. In Spry1^‐/‐ ? wild‐type chimeras, cells lacking Spry1 (a negative regulator of Ret and FGF receptor signaling) preferentially occupied the UB tips, as previously observed in traditional chimeras, thus validating this experimental system. In Fgfr2^UB‐/‐ ? wild‐type chimeras, the wild‐type cells preferentially occupied the tips. Independent evidence for a role of Fgfr2 in UB tip formation was obtained using Mosaic mutant Analysis with Spatial and Temporal control of Recombination (MASTR). Conclusions : Dissociation and reaggregation of fetal kidney cells of different genotypes, with suitable fluorescent markers, provides an efficient way to analyze cell behaviors in chimeric cultures. FGF/Fgfr2 signaling promotes UB cell rearrangements that form the tip domain, similarly to GDNF/Ret signaling. Developmental Dynamics 245:483–496, 2016. © 2015 Wiley Periodicals, Inc.     

Mesenchymal fibroblast growth factor receptor signaling regulates palatal shelf elevation during secondary palate formation

Background : Palatal shelf elevation is an essential morphogenetic process during secondary palate closure and failure or delay of palatal shelf elevation is a common cause of cleft palate, one of the most common birth defects in humans. Here, we studied the role of mesenchymal fibroblast growth factor receptor (FGFR) signaling during palate development by conditional inactivation of Fgfrs using a mesenchyme‐specific Dermo1‐Cre driver. Results : We showed that Fgfr1 is expressed throughout the palatal mesenchyme and Fgfr2 is expressed in the medial aspect of the posterior palatal mesenchyme overlapping with Fgfr1. Mesenchyme‐specific disruption of Fgfr1 and Fgfr2 affected palatal shelf elevation and resulted in cleft palate. We further showed that both Fgfr1 and Fgfr2 are expressed in mesenchymal tissues of the mandibular process but display distinct expression patterns. Loss of mesenchymal FGFR signaling reduced mandibular ossification and lower jaw growth resulting in abnormal tongue insertion in the oral‐nasal cavity. Conclusions : We propose a model to explain how redundant Fgfr1 and Fgfr2 expression in the palatal and mandibular mesenchyme regulates shelf medial wall protrusion and growth of the mandible to coordinate the craniofacial tissue movements that are required for palatal shelf elevation. Developmental Dynamics 244:1427–1438, 2015. © 2015 Wiley Periodicals, Inc.     

Ectrodactyly and Lethal Pulmonary Acinar Dysplasia Associated with Homozygous FGFR2 Mutations Identified by Exome Sequencing

Ectrodactyly/split hand‐foot malformation is genetically heterogeneous with more than 100 syndromic associations. Acinar dysplasia is a rare congenital lung lesion of unknown etiology, which is frequently lethal postnatally. To date, there have been no reports of combinations of these two phenotypes. Here, we present an infant from a consanguineous union with both ectrodactyly and autopsy confirmed acinar dysplasia. SNP array and whole‐exome sequencing analyses of the affected infant identified a novel homozygous Fibroblast Growth Factor Receptor 2 (FGFR2) missense mutation (p.R255Q) in the IgIII domain (D3). Expression studies of Fgfr2 in development show localization to the affected limbs and organs. Molecular modeling and genetic and functional assays support that this mutation is at least a partial loss‐of‐function mutation, and contributes to ectrodactyly and acinar dysplasia only in homozygosity, unlike previously reported heterozygous activating FGFR2 mutations that cause Crouzon, Apert, and Pfeiffer syndromes. This is the first report of mutations in a human disease with ectrodactyly with pulmonary acinar dysplasia and, as such, homozygous loss‐of‐function FGFR2 mutations represent a unique syndrome.     

Severe craniosynostosis in an infant with deletion 22q11.2 syndrome

We report a male infant with 22q11.2 deletion syndrome and very severe multi‐sutural craniosynostosis associated with increased intracranial pressure, marked displacement of brain structures, and extensive erosion of the skull. While uni‐ or bi‐sultural craniosynostosis is a recognized (though relatively uncommon) feature of 22q11 deletion syndrome, a severe multi‐sutural presentation of this nature has never been reported. SNP Microarray was otherwise normal and the patient did not have common mutations in FGFR2, FGFR3, or TWIST associated with craniosynostosis. While markedly variable expressivity is an acknowledged feature of deletion 22q11 syndrome, herein we also consider and discuss the possibility that this infant may have been additionally affected with an undiagnosed single gene disorder. © 2012 Wiley Periodicals, Inc.     

Oligodendrocyte‐specific deletion of FGFR2 ameliorates MOG35‐55‐induced EAE through ERK and Akt signalling

Fibroblast growth factors (FGFs) and their receptors (FGFRs) are involved in demyelinating pathologies including multiple sclerosis (MS). In our recent study, oligodendrocyte‐specific deletion of FGFR1 resulted in a milder disease course, less inflammation, reduced myelin and axon damage in EAE. The objective of this study was to elucidate the role of oligodendroglial FGFR2 in MOG_35‐55‐induced EAE. Oligodendrocyte‐specific knockout of FGFR2 (Fgfr2^{ind −/−}) was achieved by application of tamoxifen; EAE was induced using the MOG_35‐55 peptide. EAE symptoms were monitored over 62 days. Spinal cord tissue was analysed by histology, immunohistochemistry and western blot. Fgfr2^{ind −/−} mice revealed a milder disease course, less myelin damage and enhanced axonal density. The number of oligodendrocytes was not affected in demyelinated areas. However, protein expression of FGFR2, FGF2 and FGF9 was downregulated in Fgfr2^{ind −/−} mice. FGF/FGFR dependent signalling proteins were differentially regulated; pAkt was upregulated and pERK was downregulated in Fgfr2^{ind −/−} mice. The number of CD3(+) T cells, Mac3(+) cells and B220(+) B cells was less in demyelinated lesions of Fgfr2^{ind −/−} mice. Furthermore, expression of IL‐1β, TNF‐α and CD200 was less in Fgfr2^{ind −/−} mice than controls. Fgfr2^{ind −/−} mice showed an upregulation of PLP and downregulation of the remyelination inhibitors SEMA3A and TGF‐β expression. These data suggest that cell‐specific deletion of FGFR2 in oligodendrocytes has anti‐inflammatory and neuroprotective effects accompanied by changes in FGF/FGFR dependent signalling, inflammatory cytokines and expression of remyelination inhibitors. Thus, FGFRs in oligodendrocytes may represent potential targets for the treatment of inflammatory and demyelinating diseases including MS.     

The effect of a Beare‐Stevenson syndrome Fgfr2 Y394C mutation on early craniofacial bone volume and relative bone mineral density in mice

Quantifying the craniofacial skeletal phenotype during development highlights potential effects of known mutations on bone maturation and is an informative first step for the analysis of animal models. We introduce a novel technique to easily and efficiently quantify individual cranial bone volume and relative bone mineral density across the murine skull from high resolution computed tomography images. The approach can be combined with existing quantitative morphometric methods to provide details of bone growth and bone quality, which can be used to make inferences about regulatory effects local to individual bones and identify locations and developmental times for which additional analyses are warranted. Analysis of the Fgfr2^+/Y394C mouse model of Beare‐Stevenson cutis gyrata syndrome, an FGFR‐related craniosynostosis syndrome, is used to demonstrate the method. Mutants and unaffected littermates display similar bone volume and relative bone density at birth, followed by significant differences at postnatal day eight. The change in rates of bone volume growth occurs similarly for all bones of the skull, regardless of origin, location or association with craniosynostosis. These results suggest an association between low bone density, low bone volume, and Fgfr craniosynostosis mutations. Our novel technique provides an initial quantitative evaluation of local shifts in bone maturation across the skull of animal models.