{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T10:29:30Z","timestamp":1784543370621,"version":"3.55.0"},"reference-count":50,"publisher":"The Company of Biologists","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2006,1,15]]},"abstract":"<jats:p>The murine frontal bone derives entirely from the cranial neural crest(CNC) and consists of the calvarial (lateral) aspect that covers the frontal lobe of brain and the orbital aspect that forms the roof of bony orbit. TGF\u03b2 and FGF signaling have important regulatory roles in postnatal calvarial development. Our previous study has demonstrated that conditional inactivation of Tgfbr2 in the neural crest results in severe defects in calvarial development, although the cellular and molecular mechanisms by which TGF\u03b2 signaling regulates the fate of CNC cells during frontal bone development remain unknown. Here, we show that TGF\u03b2 IIR is required for proliferation of osteoprogenitor cells in the CNC-derived frontal bone anlagen. FGF acts downstream of TGF\u03b2 signaling in regulating CNC cell proliferation, and exogenous FGF2 rescues the cell proliferation defect in the frontal primordium of Tgfbr2 mutant. Furthermore, the CNC-derived frontal primordium requires TGF\u03b2 IIR to undergo terminal differentiation. However, this requirement is restricted to the developing calvarial aspect of the frontal bone, whereas the orbital aspect forms despite the ablation of Tgfbr2 gene, implying a differential requirement for TGF\u03b2signaling during the development of various regions of the frontal bone. This study demonstrates the biological significance of TGF\u03b2-mediated FGF signaling cascade in regulating frontal bone development, suggests that TGF\u03b2 functions as a morphogen in regulating the fate of the CNC-derived osteoblast and provides a model for investigating abnormal craniofacial development.<\/jats:p>","DOI":"10.1242\/dev.02200","type":"journal-article","created":{"date-parts":[[2005,12,20]],"date-time":"2005-12-20T16:23:03Z","timestamp":1135095783000},"page":"371-381","source":"Crossref","is-referenced-by-count":83,"title":["TGF\u03b2-mediated FGF signaling is crucial for regulating cranial neural crest cell proliferation during frontal bone development"],"prefix":"10.1242","volume":"133","author":[{"given":"Tomoyo","family":"Sasaki","sequence":"first","affiliation":[{"name":"Center for Craniofacial Molecular Biology School of Dentistry University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA 90033,USA."},{"name":"Division of Oral Anatomy, Department of Oral Biological Science, Niigata University Graduate School of Medical and Dental Sciences, Gakkocho-dori,Niigata 951-8514, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihiro","family":"Ito","sequence":"additional","affiliation":[{"name":"Center for Craniofacial Molecular Biology School of Dentistry University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA 90033,USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr","given":"Pablo","family":"Bringas","sequence":"additional","affiliation":[{"name":"Center for Craniofacial Molecular Biology School of Dentistry University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA 90033,USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanley","family":"Chou","sequence":"additional","affiliation":[{"name":"Center for Craniofacial Molecular Biology School of Dentistry University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA 90033,USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark M.","family":"Urata","sequence":"additional","affiliation":[{"name":"Center for Craniofacial Molecular Biology School of Dentistry University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA 90033,USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harold","family":"Slavkin","sequence":"additional","affiliation":[{"name":"Center for Craniofacial Molecular Biology School of Dentistry University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA 90033,USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Chai","sequence":"additional","affiliation":[{"name":"Center for Craniofacial Molecular Biology School of Dentistry University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA 90033,USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042605291303900_REF1","doi-asserted-by":"crossref","unstructured":"Acampora, D., Merlo, G. R., Paleari, L., Zerega, B.,Postiglione, M. P., Mantero, S., Bober, E., Barbieri, O., Simeone, A. and Levi, G. (1999). Craniofacial, vestibular and bone defects in mice lacking the Distal-less-related gene Dlx5. Development126,3795-3809.","DOI":"10.1242\/dev.126.17.3795"},{"key":"2021042605291303900_REF2","doi-asserted-by":"crossref","unstructured":"Attisano, L., Carcamo, J., Ventura, F., Weis, F. M., Massague,J. and Wrana, J. L. (1993). Identification of human activin and TGF beta type I receptors that form heteromeric kinase complexes with type II receptors. Cell75,671-680.","DOI":"10.1016\/0092-8674(93)90488-C"},{"key":"2021042605291303900_REF3","doi-asserted-by":"crossref","unstructured":"Bialek, P., Kern, B., Yang, X., Schrock, M., Sosic, D., Hong,N., Wu, H., Yu, K., Ornitz, D. M., Olson, E. N. et al.(2004). A twist code determines the onset of osteoblast differentiation. Dev. Cell6, 423-435.","DOI":"10.1016\/S1534-5807(04)00058-9"},{"key":"2021042605291303900_REF4","doi-asserted-by":"crossref","unstructured":"Chai, Y., Jiang, X., Ito, Y., Bringas, P., Jr, Han, J., Rowitch,D. H., Soriano, P., McMahon, A. P. and Sucov, H. M. (2000). Fate of the mammalian cranial neural crest during tooth and mandibular morphogenesis. Development127,1671-1679.","DOI":"10.1242\/dev.127.8.1671"},{"key":"2021042605291303900_REF5","doi-asserted-by":"crossref","unstructured":"Chen, Z. F. and Behringer, R. R. (1995). twist is required in head mesenchyme for cranial neural tube morphogenesis. Genes Dev.9,686-699.","DOI":"10.1101\/gad.9.6.686"},{"key":"2021042605291303900_REF6","doi-asserted-by":"crossref","unstructured":"Chytil, A., Magnuson, M. A., Wright, C. V. and Moses, H. L.(2002). Conditional inactivation of the TGF-beta type II receptor using Cre:Lox. Genesis32, 73-75.","DOI":"10.1002\/gene.10046"},{"key":"2021042605291303900_REF7","doi-asserted-by":"crossref","unstructured":"Danielian, P. S., Muccino, D., Rowitch, D. H., Michael, S. K. and McMahon, A. P. (1998). Modification of gene activity in mouse embryos in utero by a tamoxifen-inducible form of Cre recombinase. Curr. Biol.8,1323-1326.","DOI":"10.1016\/S0960-9822(07)00562-3"},{"key":"2021042605291303900_REF8","doi-asserted-by":"crossref","unstructured":"Delezoide, A. L., Benoist-Lasselin, C., Legeai-Mallet, L., Le Merrer, M., Munnich, A., Vekemans, M. and Bonaventure, J.(1998). Spatio-temporal expression of FGFR 1, 2 and 3 genes during human embryo-fetal ossification. Mech. Dev.77,19-30.","DOI":"10.1016\/S0925-4773(98)00133-6"},{"key":"2021042605291303900_REF9","doi-asserted-by":"crossref","unstructured":"Depew, M. J., Liu, J. K., Long, J. E., Presley, R., Meneses, J. J., Pedersen, R. A. and Rubenstein, J. L. (1999). Dlx5 regulates regional development of the branchial arches and sensory capsules. Development126,3831-3846.","DOI":"10.1242\/dev.126.17.3831"},{"key":"2021042605291303900_REF10","doi-asserted-by":"crossref","unstructured":"Depew, M. J., Lufkin, T. and Rubenstein, J. L.(2002). Specification of jaw subdivisions by Dlx genes. Science298,381-385.","DOI":"10.1126\/science.1075703"},{"key":"2021042605291303900_REF11","doi-asserted-by":"crossref","unstructured":"Derynck, R. and Zhang, Y. (1996). Intracellular signalling: the mad way to do it. Curr. Biol.6,1226-1229.","DOI":"10.1016\/S0960-9822(96)00702-6"},{"key":"2021042605291303900_REF12","doi-asserted-by":"crossref","unstructured":"Dickson, M. C., Martin, J. S., Cousins, F. M., Kulkarni, A. B.,Karlsson, S. and Akhurst, R. J. (1995). Defective haematopoiesis and vasculogenesis in transforming growth factor-beta 1 knock out mice. Development121,1845-1854.","DOI":"10.1242\/dev.121.6.1845"},{"key":"2021042605291303900_REF13","unstructured":"Dunker, N. and Krieglstein, K. (2002). Tgfbeta2-\/- Tgfbeta3 -\/- double knockout mice display severe midline fusion defects and early embryonic lethality. Anat. Embryol.206, 73-83."},{"key":"2021042605291303900_REF14","unstructured":"Eickelberg, O., Centrella, M., Reiss, M., Kashgarian, M. and Wells, R. G. (2002). Betaglycan inhibits TGF-beta signaling by preventing type I-type II receptor complex formation. Glycosaminoglycan modifications alter betaglycan function. J. Biol. Chem.277,823-829."},{"key":"2021042605291303900_REF15","doi-asserted-by":"crossref","unstructured":"el Ghouzzi, V., Le Merrer, M., Perrin-Schmitt, F., Lajeunie, E.,Benit, P., Renier, D., Bourgeois, P., Bolcato-Bellemin, A. L., Munnich, A. and Bonaventure, J. (1997). Mutations of the TWIST gene in the Saethre-Chotzen syndrome. Nat. Genet.15, 42-46.","DOI":"10.1038\/ng0197-42"},{"key":"2021042605291303900_REF16","unstructured":"Filvaroff, E., Erlebacher, A., Ye, J., Gitelman, S. E., Lotz,J., Heillman, M. and Derynck, R. (1999). Inhibition of TGF-beta receptor signaling in osteoblasts leads to decreased bone remodeling and increased trabecular bone mass. Development126,4267-4279."},{"key":"2021042605291303900_REF17","doi-asserted-by":"crossref","unstructured":"Fitzpatrick, D. R., Denhez, F., Kondaiah, P. and Akhurst, R. J. (1990). Differential expression of TGF beta isoforms in murine palatogenesis. Development109,585-595.","DOI":"10.1242\/dev.109.3.585"},{"key":"2021042605291303900_REF18","doi-asserted-by":"crossref","unstructured":"Francis-West, P., Ladher, R., Barlow, A. and Graveson, A.(1998). Signalling interactions during facial development. Mech. Dev.75,3-28.","DOI":"10.1016\/S0925-4773(98)00082-3"},{"key":"2021042605291303900_REF19","unstructured":"Greenwald, J. A., Mehrara, B. J., Spector, J. A., Fagenholz, P. J., Saadeh, P. B., Steinbrech, D. S., Gittes, G. K. and Longaker, M. T.(2000). Immature versus mature dura mater: II. Differential expression of genes important to calvarial reossification. Plast. Reconstr. Surg.106,630-639."},{"key":"2021042605291303900_REF20","unstructured":"Hall, B. K. and Ekanayake, S. (1991). Effects of growth factors on the differentiation of neural crest cells and neural crest cell-derivatives. Int. J. Dev. Biol.35,367-387."},{"key":"2021042605291303900_REF21","doi-asserted-by":"crossref","unstructured":"Holleville, N., Quilhac, A., Bontoux, M. and Monsoro-Burq, A. H. (2003). BMP signals regulate Dlx5 during early avian skull development. Dev. Biol.257,177-189.","DOI":"10.1016\/S0012-1606(03)00059-9"},{"key":"2021042605291303900_REF22","doi-asserted-by":"crossref","unstructured":"Howard, T. D., Paznekas, W. A., Green, E. D., Chiang, L. C., Ma,N., Ortiz de Luna, R. I., Garcia Delgado, C., Gonzalez-Ramos, M., Kline, A. D. and Jabs, E. W. (1997). Mutations in TWIST, a basic helix-loop-helix transcription factor, in Saethre-Chotzen syndrome. Nat. Genet.15,36-41.","DOI":"10.1038\/ng0197-36"},{"key":"2021042605291303900_REF23","doi-asserted-by":"crossref","unstructured":"Iseki, S., Osumi-Yamashita, N., Miyazono, K., Franzen, P.,Ichijo, H., Ohtani, H., Hayashi, Y. and Eto, K. (1995). Localization of transforming growth factor-beta type I and type II receptors in mouse development. Exp. Cell Res.219,339-347.","DOI":"10.1006\/excr.1995.1237"},{"key":"2021042605291303900_REF24","doi-asserted-by":"crossref","unstructured":"Ito, Y., Yeo, J. Y., Chytil, A., Han, J., Bringas, P., Jr,Nakajima, A., Shuler, C. F., Moses, H. L. and Chai, Y.(2003). Conditional inactivation of Tgfbr2 in cranial neural crest causes cleft palate and calvaria defects. Development130,5269-5280.","DOI":"10.1242\/dev.00708"},{"key":"2021042605291303900_REF25","doi-asserted-by":"crossref","unstructured":"Jabs, E. W. (2001). A TWIST in the fate of human osteoblasts identifies signaling molecules involved in skull development. J. Clin. Invest.107,1075-1077.","DOI":"10.1172\/JCI12853"},{"key":"2021042605291303900_REF26","doi-asserted-by":"crossref","unstructured":"Jiang, X., Iseki, S., Maxson, R. E., Sucov, H. M. and Morriss-Kay, G. M. (2002). Tissue origins and interactions in the mammalian skull vault. Dev. Biol.241,106-116.","DOI":"10.1006\/dbio.2001.0487"},{"key":"2021042605291303900_REF27","doi-asserted-by":"crossref","unstructured":"Kim, Y. J., Lee, M. H., Wozney, J. M., Cho, J. Y. and Ryoo, H. M. (2004). Bone morphogenetic protein-2-induced alkaline phosphatase expression is stimulated by Dlx5 and repressed by Msx2. J. Biol. Chem.279,50773-50780.","DOI":"10.1074\/jbc.M404145200"},{"key":"2021042605291303900_REF28","unstructured":"Lawler, S., Candia, A. F., Ebner, R., Shum, L., Lopez, A. R.,Moses, H. L., Wright, C. V. and Derynck, R. (1994). The murine type II TGF-beta receptor has a coincident embryonic expression and binding preference for TGF-beta 1. Development120,165-175."},{"key":"2021042605291303900_REF29","doi-asserted-by":"crossref","unstructured":"Liu, Y., Festing, M., Thompson, J. C., Hester, M., Rankin, S.,El-Hodiri, H. M., Zorn, A. M. and Weinstein, M. (2004). Smad2 and Smad3 coordinately regulate craniofacial and endodermal development. Dev. Biol.270,411-426.","DOI":"10.1016\/j.ydbio.2004.03.017"},{"key":"2021042605291303900_REF30","doi-asserted-by":"crossref","unstructured":"Loeys, B. L., Chen, J., Neptune, E. R., Judge, D. P., Podowski,M., Holm, T., Meyers, J., Leitch, C. C., Katsanis, N., Sharifi, N. et al.(2005). A syndrome of altered cardiovascular, craniofacial,neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat. Genet.37,275-281.","DOI":"10.1038\/ng1511"},{"key":"2021042605291303900_REF31","doi-asserted-by":"crossref","unstructured":"Massague, J. (1992). Receptors for the TGF-beta family. Cell69,1067-1070.","DOI":"10.1016\/0092-8674(92)90627-O"},{"key":"2021042605291303900_REF32","doi-asserted-by":"crossref","unstructured":"Massague, J. (1998). TGF-beta signal transduction. Annu. Rev. Biochem.67,753-791.","DOI":"10.1146\/annurev.biochem.67.1.753"},{"key":"2021042605291303900_REF33","doi-asserted-by":"crossref","unstructured":"Moses, H. L. and Serra, R. (1996). Regulation of differentiation by TGF-beta. Curr. Opin. Genet. Dev.6,581-586.","DOI":"10.1016\/S0959-437X(96)80087-6"},{"key":"2021042605291303900_REF34","doi-asserted-by":"crossref","unstructured":"Nakashima, K., Zhou, X., Kunkel, G., Zhang, Z., Deng, J. M.,Behringer, R. R. and de Crombrugghe, B. (2002). The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell108, 17-29.","DOI":"10.1016\/S0092-8674(01)00622-5"},{"key":"2021042605291303900_REF35","doi-asserted-by":"crossref","unstructured":"Newberry, E. P., Latifi, T. and Towler, D. A.(1998). Reciprocal regulation of osteocalcin transcription by the homeodomain proteins Msx2 and Dlx5. Biochemistry37,16360-16368.","DOI":"10.1021\/bi981878u"},{"key":"2021042605291303900_REF36","doi-asserted-by":"crossref","unstructured":"Opperman, L. A., Adab, K. and Gakunga, P. T.(2000). Transforming growth factor-beta 2 and TGF-beta 3 regulate fetal rat cranial suture morphogenesis by regulating rates of cell proliferation and apoptosis. Dev. Dyn.219,237-247.","DOI":"10.1002\/1097-0177(2000)9999:9999<::AID-DVDY1044>3.0.CO;2-F"},{"key":"2021042605291303900_REF37","doi-asserted-by":"crossref","unstructured":"Ornitz, D. M. and Marie, P. J. (2002). FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease. Genes Dev.16,1446-1465.","DOI":"10.1101\/gad.990702"},{"key":"2021042605291303900_REF38","unstructured":"Orr-Urtreger, A., Givol, D., Yayon, A., Yarden, Y. and Lonai,P. (1991). Developmental expression of two murine fibroblast growth factor receptors, flg and bek. Development113,1419-1434."},{"key":"2021042605291303900_REF39","doi-asserted-by":"crossref","unstructured":"Pelton, R. W., Hogan, B. L., Miller, D. A. and Moses, H. L.(1990). Differential expression of genes encoding TGFs beta 1, beta 2, and beta 3 during murine palate formation. Dev. Biol.141,456-460.","DOI":"10.1016\/0012-1606(90)90401-4"},{"key":"2021042605291303900_REF40","doi-asserted-by":"crossref","unstructured":"Pelton, R. W., Saxena, B., Jones, M., Moses, H. L. and Gold, L. I. (1991). Immunohistochemical localization of TGF beta 1,TGF beta 2, and TGF beta 3 in the mouse embryo: expression patterns suggest multiple roles during embryonic development. J. Cell Biol.115,1091-1105.","DOI":"10.1083\/jcb.115.4.1091"},{"key":"2021042605291303900_REF41","doi-asserted-by":"crossref","unstructured":"Rice, D. P., Aberg, T., Chan, Y., Tang, Z., Kettunen, P. J.,Pakarinen, L., Maxson, R. E. and Thesleff, I. (2000). Integration of FGF and TWIST in calvarial bone and suture development. Development127,1845-1855.","DOI":"10.1242\/dev.127.9.1845"},{"key":"2021042605291303900_REF42","doi-asserted-by":"crossref","unstructured":"Ryoo, H. M., Hoffmann, H. M., Beumer, T., Frenkel, B., Towler,D. A., Stein, G. S., Stein, J. L., van Wijnen, A. J. and Lian, J. B.(1997). Stage-specific expression of Dlx-5 during osteoblast differentiation: involvement in regulation of osteocalcin gene expression. Mol. Endocrinol.11,1681-1694.","DOI":"10.1210\/mend.11.11.0011"},{"key":"2021042605291303900_REF43","unstructured":"Sanford, L. P., Ormsby, I., Gittenberger-de Groot, A. C.,Sariola, H., Friedman, R., Boivin, G. P., Cardell, E. L. and Doetschman,T. (1997). TGFbeta2 knockout mice have multiple developmental defects that are non-overlapping with other TGFbeta knockout phenotypes. Development124,2659-2670."},{"key":"2021042605291303900_REF44","doi-asserted-by":"crossref","unstructured":"Soriano, P. (1999). Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat. Genet.21, 70-71.","DOI":"10.1038\/5007"},{"key":"2021042605291303900_REF45","doi-asserted-by":"crossref","unstructured":"Tadic, T., Dodig, M., Erceg, I., Marijanovic, I., Mina, M.,Kalajzic, Z., Velonis, D., Kronenberg, M. S., Kosher, R. A., Ferrari, D. et al. (2002). Overexpression of Dlx5 in chicken calvarial cells accelerates osteoblastic differentiation. J. Bone Miner. Res.17,1008-1014.","DOI":"10.1359\/jbmr.2002.17.6.1008"},{"key":"2021042605291303900_REF46","doi-asserted-by":"crossref","unstructured":"Wilkie, A. O. and Morriss-Kay, G. M. (2001). Genetics of craniofacial development and malformation. Nat. Rev. Genet.2,458-468.","DOI":"10.1038\/35076601"},{"key":"2021042605291303900_","doi-asserted-by":"crossref","unstructured":"Wilkinson, D. G. (1998). In Situ Hybridization: A Practical Approach. Oxford: Oxford University Press.","DOI":"10.1093\/oso\/9780199636594.001.0001"},{"key":"2021042605291303900_REF48","doi-asserted-by":"crossref","unstructured":"Wrana, J. L., Attisano, L., Carcamo, J., Zentella, A., Doody,J., Laiho, M., Wang, X. F. and Massague, J. (1992). TGF beta signals through a heteromeric protein kinase receptor complex. Cell71,1003-1014.","DOI":"10.1016\/0092-8674(92)90395-S"},{"key":"2021042605291303900_REF49","doi-asserted-by":"crossref","unstructured":"Wrana, J. L., Attisano, L., Wieser, R., Ventura, F. and Massague, J. (1994). Mechanism of activation of the TGF-beta receptor. Nature370,341-347.","DOI":"10.1038\/370341a0"},{"key":"2021042605291303900_REF50","doi-asserted-by":"crossref","unstructured":"Yu, K., Xu, J., Liu, Z., Sosic, D., Shao, J., Olson, E. N.,Towler, D. A. and Ornitz, D. M. (2003). Conditional inactivation of FGF receptor 2 reveals an essential role for FGF signaling in the regulation of osteoblast function and bone growth. Development130,3063-3074.","DOI":"10.1242\/dev.00491"}],"container-title":["Development"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/133\/2\/371\/1471863\/371.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/133\/2\/371\/1471863\/371.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,1]],"date-time":"2024-02-01T16:14:48Z","timestamp":1706804088000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dev\/article\/133\/2\/371\/43187\/TGF-mediated-FGF-signaling-is-crucial-for"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2006,1,15]]},"references-count":50,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2006,1,15]]}},"URL":"https:\/\/doi.org\/10.1242\/dev.02200","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.1029930.347669","asserted-by":"object"}]},"ISSN":["1477-9129","0950-1991"],"issn-type":[{"value":"1477-9129","type":"electronic"},{"value":"0950-1991","type":"print"}],"subject":[],"published":{"date-parts":[[2006,1,15]]}}}