A gain-of-function mutation of
            <i>Fgfr2c</i>
            demonstrates the roles of this receptor variant in osteogenesis

Eswarakumar, Veraragavan P.; Horowitz, Mark C.; Locklin, R M; Morriss‐Kay, Gillian M.; Lonai, Peter

doi:10.1073/pnas.0405031101

Cited by 201 publications

(240 citation statements)

References 30 publications

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“…For instance, abnormal cranial bases in achondroplasia and Apert, Crouzon, and Muenke syndromes are caused by mutations in FGFR, indicating that FGF signaling is not only important to the formation of the cranial vault, but also for the cranial base (Horowitz, 1981;Cohen et al, 1985;Kreiborg et al, 1993Kreiborg et al, , 1999Wilkie and Morriss-Kay, 2001;Reinhart et al, 2003). Similar defects have been observed in FGFR transgenic mouse strains Eswarakumar et al, 2002Eswarakumar et al, , 2004. Mutations in RUNX2 and TWIST give rise to cleidocranial dysplasia and Saethre-Chotzen syndromes, respectively, which are characterized by defects in the cranial base (Evans and Christiansen, 1976;Kreiborg et al, 1981;Howard et al, 1997;Lee et al, 1997).…”

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confidence: 60%

Histological development and dynamic expression of Bmp2–6 mRNAs in the embryonic and postnatal mousecranial base

et al. 2006

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The cranial base is formed by endochondral ossification and is characterized by the presence of the synchondrosis growth centers. The aim of this study was to describe the histological development of the mouse midsagittal cranial base area from embryonic day 10 (E10) to the postnatal age of 2 months. The Bmp family of signaling molecules serves important functions in embryo and bone development and may therefore play a significant role in the early formation of the cranial base. To investigate this, we analyzed the mRNA pattern of expression of Bmp2-6 in the mouse cranial base from E10 to 5 days postnatally using radioactive in situ hybridization. We found that the formation of the mouse cranial base corresponds to that of rat and proceeds in a caudorostral sequence. Moreover, all Bmps studied showed distinct and overlapping developmentally regulated expression domains. Bmp2, Bmp5, and Bmp6 were expressed in the early mesenchymal condensations. Later, Bmp2, Bmp3, Bmp4, and Bmp5 were detected in the perichondrium and in the adjacent mesenchyme. Subsequently, Bmp2 and Bmp6 expressions were confined to hypertrophic chondrocytes, while Bmp3, Bmp4, and Bmp5 were expressed in the osteoblasts of the trabecular bone and bone collar. Interestingly, Bmp3 was uniquely expressed postnatally in the resting zone of the synchondrosis growth center, suggesting a role in the regulation of cranial base growth. These results suggest that Bmp signaling may serve specific and synergistic functions at different key stages of cranial base development and growth. Anat Rec Part A, 288A:1250-1258, 2006. 2006 Key words: bone morphogenetic proteins; skeletogenesis; endochondral bone; hard tissue; growth; synchondrosisThe cranial base, which is located between the brain and the facial bones, forms the floor of the neurocranium and is established by the coordinated development and growth of several skeletal elements. The human midline cranial base is composed of the basioccipital, sphenoid, ethmoid, and frontal bones (Scott, 1958). The cranial base is an important growth center of the head and is believed to play a significant role in the integration of craniofacial development and growth.In contrast to the bones of the cranial vault and the face, which are formed by intramembranous ossification, the midline cranial base bones, like the long bones, the vertebrae, and the ribcage, are formed by endochondral ossification. However,

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confidence: 60%

Histological development and dynamic expression of Bmp2–6 mRNAs in the embryonic and postnatal mousecranial base

et al. 2006

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“…Furthermore, we also showed that FGF-2 controls NAMP function in culture through FGFR2c. Interestingly, gain-of-function mutations of FGFR2c, which is expressed during osteogenesis [47], caused impaired differentiation of BM osteoprogenitors and osteoblasts [48], leading to bone malformations characteristic of the Crouzon and Pfeiffer syndromes in patients [49]. Conversely, in FGFR2c À/ À mice, the balance between proliferation and differentiation of skeletal progenitors was shown to be shifted toward differentiation, leading to premature loss of osteoprogenitor selfrenewal and early termination of bone formation [50].…”

Section: Discussionmentioning

confidence: 99%

Fibroblast Growth Factor-2 Maintains a Niche-Dependent Population of Self-Renewing Highly Potent Non-adherent Mesenchymal Progenitors Through FGFR2c

et al. 2012

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Bone marrow (BM) mesenchymal stem/stromal cells (MSC) are a heterogeneous population of multipotent progenitors currently under investigation for a variety of applications in regenerative medicine. While self-renewal of stem cells in different tissues has been demonstrated to be regulated by specialized microenvironments called niches, it is still unclear whether a self-renewing niche also exists for MSC. Here, we show that primary human BM cultures contain a population of intrinsically non-adherent mesenchymal progenitors (NAMP) with features of more primitive progenitors than the initially adhering colonyforming units-fibroblast (CFU-f). In fact, NAMP could generate an adherent progeny: (a) enriched with early mesenchymal populations (CD1461, SSEA-11, and SSEA-41); (b) with significantly greater proliferation and multilineage differentiation potential in vitro; and (c) capable of threefold greater bone formation in vivo than the corresponding CFU-f. Upon serial replating, NAMP were able to regenerate and expand in suspension as non-adherent clonogenic progenitors, while also giving rise to an adherent progeny. This took place at the cost of a gradual loss of proliferative potential, shown by a reduction in colony size, which could be completely prevented when NAMP were expanded on the initially adhering BM fraction. Mechanistically, we found that NAMP crucially depend on fibroblast growth factor (FGF)-2 signaling through FGFR2c for their survival and expansion. Furthermore, NAMP maintenance depends at least in part on humoral signals distinct from FGF-2. In conclusion, our data show a niche/progenitor organization in vitro, in which the BM adherent fraction provides a self-renewing microenvironment for primitive NAMP.

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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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A gain-of-function mutation of Fgfr2c demonstrates the roles of this receptor variant in osteogenesis

Cited by 201 publications

References 30 publications

Histological development and dynamic expression of Bmp2–6 mRNAs in the embryonic and postnatal mousecranial base

Histological development and dynamic expression of Bmp2–6 mRNAs in the embryonic and postnatal mousecranial base

Fibroblast Growth Factor-2 Maintains a Niche-Dependent Population of Self-Renewing Highly Potent Non-adherent Mesenchymal Progenitors Through FGFR2c

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

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