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Craniofacial, orofacial and dental disorders: the role of the RAS/ERK pathway

Published online by Cambridge University Press:  13 March 2019

Angeliki Vogiatzi  and
George Mavrothalassitis Open the ORCID record for George Mavrothalassitis [Opens in a new window]
Angeliki Vogiatzi
Affiliation:
School of Medicine, University of Crete, Crete, Greece
George Mavrothalassitis*
Affiliation:
School of Medicine, University of Crete, Crete, Greece IMBB, FORTH, Heraklion, Crete 71003, Greece
*
Corresponding author: George Mavrothalassitis E-mail: [email protected]
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Abstract

Deviations from the precisely coordinated programme of human head development can lead to craniofacial and orofacial malformations often including a variety of dental abnormalities too. Although the aetiology is still unknown in many cases, during the last decades different intracellular signalling pathways have been genetically linked to specific disorders. Among these pathways, the RAS/extracellular signal-regulated kinase (ERK) signalling cascade is the focus of this review since it encompasses a large group of genes that when mutated cause some of the most common and severe developmental anomalies in humans. We present the components of the RAS/ERK pathway implicated in craniofacial and orodental disorders through a series of human and animal studies. We attempt to unravel the specific molecular targets downstream of ERK that act on particular cell types and regulate key steps in the associated developmental processes. Finally we point to ambiguities in our current knowledge that need to be clarified before RAS/ERK-targeting therapeutic approaches can be implemented.

Keywords

Craniofacial disordersdental abnormalitiesERK signalling pathwayhead developmentorofacial abnormalities
Type
Review
Information
Expert Reviews in Molecular Medicine , Volume 21 , 2019 , e2
Copyright
Copyright © Cambridge University Press 2019 

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References

1.New, HV, Howes, G and Smith, JC (1991) Inductive interactions in early embryonic development. Current Opinion in Genetics & Development 1, 196–203.Google Scholar
2.Van Otterloo, E, Williams, T and Artinger, KB (2016) The old and new face of craniofacial research: how animal models inform human craniofacial genetic and clinical data. Developmental Biology 415, 171–187.Google Scholar
3.Neben, CL and Merrill, AE (2015) Signaling pathways in craniofacial development: insights from rare skeletal disorders. Current Topics in Developmental Biology 115, 493–542.Google Scholar
4.Schlessinger, J (2000) Cell signaling by receptor tyrosine kinases. Cell 103, 211–225.Google Scholar
5.Pawson, T (2002) Regulation and targets of receptor tyrosine kinases. European Journal of Cancer 38(Suppl 5), S3–10.Google Scholar
6.Marshall, CJ (1996) Ras effectors. Current Opinion in Cell Biology 8, 197–204.Google Scholar
7.Quilliam, LA, Khosravi-Far, R, Huff, SY and Der, CJ (1995) Guanine nucleotide exchange factors: activators of the Ras superfamily of proteins. Bioessays 17, 395–404.Google Scholar
8.Denayer, E, de Ravel, T and Legius, E (2008) Clinical and molecular aspects of RAS related disorders. Journal of Medical Genetics 45, 695–703.Google Scholar
9.Hernandez-Porras, I and Guerra, C (2017) Modeling RASopathies with genetically modified mouse models. Methods in Molecular Biology 1487, 379–408.Google Scholar
10.Bush, JO and Jiang, R (2012) Palatogenesis: morphogenetic and molecular mechanisms of secondary palate development. Development 139, 231–243.Google Scholar
11.Lan, Y, Xu, J and Jiang, R (2015) Cellular and molecular mechanisms of palatogenesis. Current Topics in Developmental Biology 115, 59–84.Google Scholar
12.Dudas, M, Li, WY, Kim, J, Yang, A and Kaartinen, V (2007) Palatal fusion – where do the midline cells go? A review on cleft palate, a major human birth defect. Acta Histochemica 109, 1–14.Google Scholar
13.Jalali, A, Zhu, X, Liu, C and Nawshad, A (2012) Induction of palate epithelial mesenchymal transition by transforming growth factor beta3 signaling. Development Growth & Differentiation 54, 633–648.Google Scholar
14.Kim, S, Lewis, AE, Singh, V, Ma, X, Adelstein, R and Bush, JO (2015) Convergence and extrusion are required for normal fusion of the mammalian secondary palate. PLoS Biology 13, e1002122.Google Scholar
15.Li, C, Lan, Y and Jiang, R (2017) Molecular and cellular mechanisms of palate development. Journal of Dental Research 96, 1184–1191.Google Scholar
16.Parada, C, Han, D, Grimaldi, A, Sarrion, P, Park, SS, Pelikan, R, Sanchez-Lara, PA and Chai, Y (2015) Disruption of the ERK/MAPK pathway in neural crest cells as a potential cause of Pierre Robin sequence. Development 142, 3734–3745.Google Scholar
17.Cho, KW, Cho, SW, Lee, JM, Lee, MJ, Gang, HS and Jung, HS (2008) Expression of phosphorylated forms of ERK, MEK, PTEN and PI3K in mouse oral development. Gene Expression Patterns: GEP 8, 284–290.Google Scholar
18.Conte, F, Oti, M, Dixon, J, Carels, CE, Rubini, M and Zhou, H (2016) Systematic analysis of copy number variants of a large cohort of orofacial cleft patients identifies candidate genes for orofacial clefts. Human Genetics 135, 41–59.Google Scholar
19.Vieira, AR, Avila, JR, Daack-Hirsch, S, Dragan, E, Felix, TM, Rahimov, F, Harrington, J, Schultz, RR, Watanabe, Y, Johnson, M, Fang, J, O'Brien, SE, Orioli, IM, Castilla, EE, Fitzpatrick, DR, Jiang, R, Marazita, ML and Murray, JC (2005) Medical sequencing of candidate genes for nonsyndromic cleft lip and palate. PLoS Genetics 1, e64.Google Scholar
20.Matsumura, K, Taketomi, T, Yoshizaki, K, Arai, S, Sanui, T, Yoshiga, D, Yoshimura, A and Nakamura, S (2011) Sprouty2 controls proliferation of palate mesenchymal cells via fibroblast growth factor signaling. Biochemical and Biophysical Research Communications 404, 1076–1082.Google Scholar
21.Bush, JO and Soriano, P (2010) Ephrin-B1 forward signaling regulates craniofacial morphogenesis by controlling cell proliferation across Eph-ephrin boundaries. Genes & Development 24, 2068–2080.Google Scholar
22.Newbern, J, Zhong, J, Wickramasinghe, RS, Li, X, Wu, Y, Samuels, I, Cherosky, N, Karlo, JC, O'Loughlin, B, Wikenheiser, J, Gargesha, M, Doughman, YQ, Charron, J, Ginty, DD, Watanabe, M, Saitta, SC, Snider, WD and Landreth, GE (2008) Mouse and human phenotypes indicate a critical conserved role for ERK2 signaling in neural crest development. Proceedings of the National Academy of Sciences of the USA 105, 17115–17120.Google Scholar
23.Kamiya, N, Shen, J, Noda, K, Kitami, M, Feng, GS, Chen, D and Komatsu, Y (2015) SHP2-Deficiency in chondrocytes deforms orofacial cartilage and ciliogenesis in mice. Journal of Bone and Mineral Research 30, 2028–2032.Google Scholar
24.Vasudevan, HN and Soriano, P (2014) SRF regulates craniofacial development through selective recruitment of MRTF cofactors by PDGF signaling. Developmental Cell 31, 332–344.Google Scholar
25.Kelly, ML, Astsaturov, A, Rhodes, J and Chernoff, J (2014) A Pak1/Erk signaling module acts through Gata6 to regulate cardiovascular development in zebrafish. Developmental Cell 29, 350–359.Google Scholar
26.Yamamoto, T, Cui, XM and Shuler, CF (2003) Role of ERK1/2 signaling during EGF-induced inhibition of palatal fusion. Developmental Biology 260, 512–521.Google Scholar
27.Morriss-Kay, GM and Wilkie, AO (2005) Growth of the normal skull vault and its alteration in craniosynostosis: insights from human genetics and experimental studies. Journal of Anatomy 207, 637–653.Google Scholar
28.Richtsmeier, JT and Flaherty, K (2013) Hand in glove: brain and skull in development and dysmorphogenesis. Acta Neuropathologica 125, 469–489.Google Scholar
29.Yoshida, T, Vivatbutsiri, P, Morriss-Kay, G, Saga, Y and Iseki, S (2008) Cell lineage in mammalian craniofacial mesenchyme. Mechanisms of Development 125, 797–808.Google Scholar
30.Twigg, SR and Wilkie, AO (2015) A genetic-pathophysiological framework for craniosynostosis. American Journal of Human Genetics 97, 359–377.Google Scholar
31.Deckelbaum, RA, Holmes, G, Zhao, Z, Tong, C, Basilico, C and Loomis, CA (2012) Regulation of cranial morphogenesis and cell fate at the neural crest-mesoderm boundary by engrailed 1. Development 139, 1346–1358.Google Scholar
32.Lana-Elola, E, Rice, R, Grigoriadis, AE and Rice, DP (2007) Cell fate specification during calvarial bone and suture development. Developmental Biology 311, 335–346.Google Scholar
33.Jiang, X, Iseki, S, Maxson, RE, Sucov, HM and Morriss-Kay, GM (2002) Tissue origins and interactions in the mammalian skull vault. Developmental Biology 241, 106–116.Google Scholar
34.Opperman, LA (2000) Cranial sutures as intramembranous bone growth sites. Developmental Dynamics 219, 472–485.Google Scholar
35.Sahar, DE, Longaker, MT and Quarto, N (2005) Sox9 neural crest determinant gene controls patterning and closure of the posterior frontal cranial suture. Developmental Biology 280, 344–361.Google Scholar
36.James, AW, Xu, Y, Lee, JK, Wang, R and Longaker, MT (2009) Differential effects of TGF-beta1 and TGF-beta3 on chondrogenesis in posterofrontal cranial suture-derived mesenchymal cells in vitro. Plastic and Reconstructive Surgery 123, 31–43.Google Scholar
37.Katsianou, MA, Adamopoulos, C, Vastardis, H and Basdra, EK (2016) Signaling mechanisms implicated in cranial sutures pathophysiology: craniosynostosis. Bba Clinical 6, 165–176.Google Scholar
38.Wilkie, AO, Slaney, SF, Oldridge, M, Poole, MD, Ashworth, GJ, Hockley, AD, Hayward, RD, David, DJ, Pulleyn, LJ, Rutland, P, Malcolm, S, Winter, RM and Reardon, W (1995) Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome. Nature Genetics 9, 165–172.Google Scholar
39.Yin, L, Du, X, Li, C, Xu, X, Chen, Z, Su, N, Zhao, L, Qi, H, Li, F, Xue, J, Yang, J, Jin, M, Deng, C and Chen, L (2008) A Pro253Arg mutation in fibroblast growth factor receptor 2 (Fgfr2) causes skeleton malformation mimicking human Apert syndrome by affecting both chondrogenesis and osteogenesis. Bone 42, 631–643.Google Scholar
40.Chen, L, Li, D, Li, C, Engel, A and Deng, CX (2003) A Ser252Trp [corrected] substitution in mouse fibroblast growth factor receptor 2 (Fgfr2) results in craniosynostosis. Bone 33, 169–178.Google Scholar
41.Shukla, V, Coumoul, X, Wang, RH, Kim, HS and Deng, CX (2007) RNA interference and inhibition of MEK-ERK signaling prevent abnormal skeletal phenotypes in a mouse model of craniosynostosis. Nature Genetics 39, 1145–1150.Google Scholar
42.Wang, Y, Sun, M, Uhlhorn, VL, Zhou, X, Peter, I, Martinez-Abadias, N, Hill, CA, Percival, CJ, Richtsmeier, JT, Huso, DL and Jabs, EW (2010) Activation of p38 MAPK pathway in the skull abnormalities of Apert syndrome Fgfr2(+P253R) mice. BMC Developmental Biology 10, 22.Google Scholar
43.Reardon, W, Winter, RM, Rutland, P, Pulleyn, LJ, Jones, BM and Malcolm, S (1994) Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome. Nature Genetics 8, 98–103.Google Scholar
44.Li, X, Young, NM, Tropp, S, Hu, D, Xu, Y, Hallgrimsson, B and Marcucio, RS (2013) Quantification of shape and cell polarity reveals a novel mechanism underlying malformations resulting from related FGF mutations during facial morphogenesis. Human Molecular Genetics 22, 5160–5172.Google Scholar
45.Pfaff, MJ, Xue, K, Li, L, Horowitz, MC, Steinbacher, DM and Eswarakumar, JVP (2016) FGFR2c-mediated ERK-MAPK activity regulates coronal suture development. Developmental Biology 415, 242–250.Google Scholar
46.Timberlake, AT, Furey, CG, Choi, J, Nelson-Williams, C, Loring, E, Galm, A, Kahle, KT, Steinbacher, DM, Larysz, D, Persing, JA and Lifton, RP (2017) De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis. Proceedings of the National Academy of Sciences of the USA 114, E7341–E7E47.Google Scholar
47.Twigg, SR, Vorgia, E, McGowan, SJ, Peraki, I, Fenwick, AL, Sharma, VP, Allegra, M, Zaragkoulias, A, Sadighi Akha, E, Knight, SJ, Lord, H, Lester, T, Izatt, L, Lampe, AK, Mohammed, SN, Stewart, FJ, Verloes, A, Wilson, LC, Healy, C, Sharpe, PT, Hammond, P, Hughes, J, Taylor, S, Johnson, D, Wall, SA, Mavrothalassitis, G and Wilkie, AO (2013) Reduced dosage of ERF causes complex craniosynostosis in humans and mice and links ERK1/2 signaling to regulation of osteogenesis. Nature Genetics 45, 308–313.Google Scholar
48.Chaudhry, A, Sabatini, P, Han, L, Ray, PN, Forrest, C and Bowdin, S (2015) Heterozygous mutations in ERF cause syndromic craniosynostosis with multiple suture involvement. American Journal of Medical Genetics. Part A 167A, 2544–2547.Google Scholar
49.Clarke, CM, Fok, VT, Gustafson, JA, Smyth, MD, Timms, AE, Frazar, CD, Smith, JD, Birgfeld, CB, Lee, A, Ellenbogen, RG, Gruss, JS, Hopper, RA and Cunningham, ML (2018) Single suture craniosynostosis: identification of rare variants in genes associated with syndromic forms. American Journal of Medical Genetics. Part A 176, 290–300.Google Scholar
50.Bezniakow, N, Gos, M and Obersztyn, E (2014) The RASopathies as an example of RAS/MAPK pathway disturbances – clinical presentation and molecular pathogenesis of selected syndromes. Developmental Period Medicine 18, 285–296.Google Scholar
51.Nakamura, T, Gulick, J, Pratt, R and Robbins, J (2009) Noonan syndrome is associated with enhanced pERK activity, the repression of which can prevent craniofacial malformations. Proceedings of the National Academy of Sciences of the USA 106, 15436–15441.Google Scholar
52.Wu, X, Simpson, J, Hong, JH, Kim, KH, Thavarajah, NK, Backx, PH, Neel, BG and Araki, T (2011) MEK-ERK pathway modulation ameliorates disease phenotypes in a mouse model of Noonan syndrome associated with the Raf1(L613V) mutation. Journal of Clinical Investigation 121, 1009–1025.Google Scholar
53.De Rocca Serra-Nedelec, A, Edouard, T, Treguer, K, Tajan, M, Araki, T, Dance, M, Mus, M, Montagner, A, Tauber, M, Salles, JP, Valet, P, Neel, BG, Raynal, P and Yart, A (2012) Noonan syndrome-causing SHP2 mutants inhibit insulin-like growth factor 1 release via growth hormone-induced ERK hyperactivation, which contributes to short stature. Proceedings of the National Academy of Sciences of the USA 109, 4257–4262.Google Scholar
54.Razzaque, MA, Komoike, Y, Nishizawa, T, Inai, K, Furutani, M, Higashinakagawa, T and Matsuoka, R (2012) characterization of a novel KRAS mutation identified in Noonan syndrome. American Journal of Medical Genetics. Part A 158A, 524–532.Google Scholar
55.Bonetti, M, Rodriguez-Martinez, V, Paardekooper Overman, J, Overvoorde, J, van Eekelen, M, Jopling, C and Hertog, J (2014) Distinct and overlapping functions of ptpn11 genes in Zebrafish development. PLoS ONE 9, e94884.Google Scholar
56.Marin, TM, Keith, K, Davies, B, Conner, DA, Guha, P, Kalaitzidis, D, Wu, X, Lauriol, J, Wang, B, Bauer, M, Bronson, R, Franchini, KG, Neel, BG and Kontaridis, MI (2011) Rapamycin reverses hypertrophic cardiomyopathy in a mouse model of LEOPARD syndrome-associated PTPN11 mutation. Journal of Clinical Investigation 121, 1026–1043.Google Scholar
57.Rodriguez-Viciana, P and Rauen, KA (2008) Biochemical characterization of novel germline BRAF and MEK mutations in cardio-facio-cutaneous syndrome. Methods in Enzymology 438, 277–289.Google Scholar
58.Inoue, S, Moriya, M, Watanabe, Y, Miyagawa-Tomita, S, Niihori, T, Oba, D, Ono, M, Kure, S, Ogura, T, Matsubara, Y and Aoki, Y (2014) New BRAF knockin mice provide a pathogenetic mechanism of developmental defects and a therapeutic approach in cardio-facio-cutaneous syndrome. Human Molecular Genetics 23, 6553–6566.Google Scholar
59.Anastasaki, C, Rauen, KA and Patton, EE (2012) Continual low-level MEK inhibition ameliorates cardio-facio-cutaneous phenotypes in zebrafish. Disease Models & Mechanisms 5, 546–552.Google Scholar
60.Pasteris, NG, Cadle, A, Logie, LJ, Porteous, ME, Schwartz, CE, Stevenson, RE, Glover, TW, Wilroy, RS and Gorski, JL (1994) Isolation and characterization of the faciogenital dysplasia (aarskog-scott syndrome) gene: a putative Rho/Rac guanine nucleotide exchange factor. Cell 79, 669–678.Google Scholar
61.Zou, W, Greenblatt, MB, Shim, JH, Kant, S, Zhai, B, Lotinun, S, Brady, N, Hu, DZ, Gygi, SP, Baron, R, Davis, RJ, Jones, D and Glimcher, LH (2011) MLK3 regulates bone development downstream of the faciogenital dysplasia protein FGD1 in mice. Journal of Clinical Investigation 121, 4383–4392.Google Scholar
62.Balasubramanian, M, Lord, H, Levesque, S, Guturu, H, Thuriot, F, Sillon, G, Wenger, AM, Sureka, DL, Lester, T, Johnson, DS, Bowen, J, Calhoun, AR, Viskochil, DH, Bejerano, G, Bernstein, JA and Chitayat, D (2017) Chitayat syndrome: hyperphalangism, characteristic facies, hallux valgus and bronchomalacia results from a recurrent c.266A > G p.(Tyr89Cys) variant in the ERF gene. Journal of Medical Genetics 54, 157–165.+G+p.(Tyr89Cys)+variant+in+the+ERF+gene.+Journal+of+Medical+Genetics+54,+157–165.>Google Scholar
63.Ng, SB, Bigham, AW, Buckingham, KJ, Hannibal, MC, McMillin, MJ, Gildersleeve, HI, Beck, AE, Tabor, HK, Cooper, GM, Mefford, HC, Lee, C, Turner, EH, Smith, JD, Rieder, MJ, Yoshiura, K, Matsumoto, N, Ohta, T, Niikawa, N, Nickerson, DA, Bamshad, MJ and Shendure, J (2010) Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nature Genetics 42, 790–793.Google Scholar
64.Lederer, D, Grisart, B, Digilio, MC, Benoit, V, Crespin, M, Ghariani, SC, Maystadt, I, Dallapiccola, B and Verellen-Dumoulin, C (2012) Deletion of KDM6A, a histone demethylase interacting with MLL2, in three patients with Kabuki syndrome. American Journal of Human Genetics 90, 119–124.Google Scholar
65.Bogershausen, N, Tsai, IC, Pohl, E, Kiper, PO, Beleggia, F, Percin, EF, Keupp, K, Matchan, A, Milz, E, Alanay, Y, Kayserili, H, Liu, Y, Banka, S, Kranz, A, Zenker, M, Wieczorek, D, Elcioglu, N, Prontera, P, Lyonnet, S, Meitinger, T, Stewart, AF, Donnai, D, Strom, TM, Boduroglu, K, Yigit, G, Li, Y, Katsanis, N and Wollnik, B (2015) RAP1-mediated MEK/ERK pathway defects in Kabuki syndrome. Journal of Clinical Investigation 125, 3585–3599.Google Scholar
66.York, RD, Yao, H, Dillon, T, Ellig, CL, Eckert, SP, McCleskey, EW and Stork, PJ (1998) Rap1 mediates sustained MAP kinase activation induced by nerve growth factor. Nature 392, 622–626.Google Scholar
67.Hu, CD, Kariya, K, Kotani, G, Shirouzu, M, Yokoyama, S and Kataoka, T (1997) Coassociation of Rap1A and Ha-Ras with Raf-1 N-terminal region interferes with ras-dependent activation of Raf-1. Journal of Biological Chemistry 272, 11702–5.Google Scholar
68.Park, J, Park, OJ, Yoon, WJ, Kim, HJ, Choi, KY, Cho, TJ and Ryoo, HM (2012) Functional characterization of a novel FGFR2 mutation, E731 K, in craniosynostosis. Journal of Cellular Biochemistry 113, 457–464.Google Scholar
69.Muenke, M, Schell, U, Hehr, A, Robin, NH, Losken, HW, Schinzel, A, Pulleyn, LJ, Rutland, P, Reardon, W, Malcolm, S and Winter, RM (1994) A common mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome. Nature Genetics 8, 269–274.Google Scholar
70.Schell, U, Hehr, A, Feldman, GJ, Robin, NH, Zackai, EH, de Die-Smulders, C, Viskochil, DH, Stewart, JM, Wolff, G, Ohashi, H, Price, RA, Cohen, MM Jr and Muenke, M (1995) Mutations in FGFR1 and FGFR2 cause familial and sporadic Pfeiffer syndrome. Human Molecular Genetics 4, 323–328.Google Scholar
71.Rutland, P, Pulleyn, LJ, Reardon, W, Baraitser, M, Hayward, R, Jones, B, Malcolm, S, Winter, RM, Oldridge, M, Slaney, SF, Poole, MD and Wilkie, AOM (1995) Identical mutations in the FGFR2 gene cause both Pfeiffer and Crouzon syndrome phenotypes. Nature Genetics 9, 173–176.Google Scholar
72.Przylepa, KA, Paznekas, W, Zhang, M, Golabi, M, Bias, W, Bamshad, MJ, Carey, JC, Hall, BD, Stevenson, R, Orlow, S, Cohen, MM Jr and Jabs, EW (1996) Fibroblast growth factor receptor 2 mutations in Beare-Stevenson cutis gyrata syndrome. Nature Genetics 13, 492–494.Google Scholar
73.Wang, Y, Zhou, X, Oberoi, K, Phelps, R, Couwenhoven, R, Sun, M, Rezza, A, Holmes, G, Percival, CJ, Friedenthal, J, Krejci, P, Richtsmeier, JT, Huso, DL, Rendl, M and Jabs, EW (2012) P38 inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice. Journal of Clinical Investigation 122, 2153–2164.Google Scholar
74.Merrill, AE, Sarukhanov, A, Krejci, P, Idoni, B, Camacho, N, Estrada, KD, Lyons, KM, Deixler, H, Robinson, H, Chitayat, D, Curry, CJ, Lachman, RS, Wilcox, WR and Krakow, D (2012) Bent bone dysplasia-FGFR2 type, a distinct skeletal disorder, has deficient canonical FGF signaling. American Journal of Human Genetics 90, 550–557.Google Scholar
75.Tartaglia, M, Mehler, EL, Goldberg, R, Zampino, G, Brunner, HG, Kremer, H, van der Burgt, I, Crosby, AH, Ion, A, Jeffery, S, Kalidas, K, Patton, MA, Kucherlapati, RS and Gelb, BD (2001) Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nature Genetics 29, 465–468.Google Scholar
76.Moncini, S, Bonati, MT, Morella, I, Ferrari, L, Brambilla, R and Riva, P (2015) Differential allelic expression of SOS1 and hyperexpression of the activating SOS1 c.755C variant in a Noonan syndrome family. European Journal of Human Genetics 23, 1531–1537.Google Scholar
77.Aoki, Y, Niihori, T, Banjo, T, Okamoto, N, Mizuno, S, Kurosawa, K, Ogata, T, Takada, F, Yano, M, Ando, T, Hoshika, T, Barnett, C, Ohashi, H, Kawame, H, Hasegawa, T, Okutani, T, Nagashima, T, Hasegawa, S, Funayama, R, Nakayama, K, Inoue, S, Watanabe, Y, Ogura, T and Matsubara, Y (2013) Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome. American Journal of Human Genetics 93, 173–180.Google Scholar
78.Digilio, MC, Conti, E, Sarkozy, A, Mingarelli, R, Dottorini, T, Marino, B, Pizzuti, A and Dallapiccola, B (2002) Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene. American Journal of Human Genetics 71, 389–394.Google Scholar
79.Pandit, B, Sarkozy, A, Pennacchio, LA, Carta, C, Oishi, K, Martinelli, S, Pogna, EA, Schackwitz, W, Ustaszewska, A, Landstrom, A, Bos, JM, Ommen, SR, Esposito, G, Lepri, F, Faul, C, Mundel, P, Lopez Siguero, JP, Tenconi, R, Selicorni, A, Rossi, C, Mazzanti, L, Torrente, I, Marino, B, Digilio, MC, Zampino, G, Ackerman, MJ, Dallapiccola, B, Tartaglia, M and Gelb, BD (2007) Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nature Genetics 39, 1007–1012.Google Scholar
80.Sarkozy, A, Carta, C, Moretti, S, Zampino, G, Digilio, MC, Pantaleoni, F, Scioletti, AP, Esposito, G, Cordeddu, V, Lepri, F, Petrangeli, V, Dentici, ML, Mancini, GM, Selicorni, A, Rossi, C, Mazzanti, L, Marino, B, Ferrero, GB, Silengo, MC, Memo, L, Stanzial, F, Faravelli, F, Stuppia, L, Puxeddu, E, Gelb, BD, Dallapiccola, B and Tartaglia, M (2009) Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum. Human Mutation 30, 695–702.Google Scholar
81.Narumi, Y, Aoki, Y, Niihori, T, Neri, G, Cave, H, Verloes, A, Nava, C, Kavamura, MI, Okamoto, N, Kurosawa, K, Hennekam, RC, Wilson, LC, Gillessen-Kaesbach, G, Wieczorek, D, Lapunzina, P, Ohashi, H, Makita, Y, Kondo, I, Tsuchiya, S, Ito, E, Sameshima, K, Kato, K, Kure, S and Matsubara, Y (2007) Molecular and clinical characterization of cardio-facio-cutaneous (CFC) syndrome: overlapping clinical manifestations with Costello syndrome. American Journal of Medical Genetics. Part A 143A, 799–807.Google Scholar
82.Niihori, T, Aoki, Y, Narumi, Y, Neri, G, Cave, H, Verloes, A, Okamoto, N, Hennekam, RC, Gillessen-Kaesbach, G, Wieczorek, D, Kavamura, MI, Kurosawa, K, Ohashi, H, Wilson, L, Heron, D, Bonneau, D, Corona, G, Kaname, T, Naritomi, K, Baumann, C, Matsumoto, N, Kato, K, Kure, S and Matsubara, Y (2006) Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome. Nature Genetics 38, 294–296.Google Scholar
83.Aoki, Y, Niihori, T, Kawame, H, Kurosawa, K, Ohashi, H, Tanaka, Y, Filocamo, M, Kato, K, Suzuki, Y, Kure, S and Matsubara, Y (2005) Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nature Genetics 37, 1038–1040.Google Scholar
84.Wallace, MR, Marchuk, DA, Andersen, LB, Letcher, R, Odeh, HM, Saulino, AM, Fountain, JW, Brereton, A, Nicholson, J, Mitchell, AL, Brownstein, BH and Collins, FS (1990) Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science 249, 181–186.Google Scholar
85.Brems, H, Chmara, M, Sahbatou, M, Denayer, E, Taniguchi, K, Kato, R, Somers, R, Messiaen, L, De Schepper, S, Fryns, JP, Cools, J, Marynen, P, Thomas, G, Yoshimura, A and Legius, E (2007) Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype. Nature Genetics 39, 1120–1126.Google Scholar
86.Eerola, I, Boon, LM, Mulliken, JB, Burrows, PE, Dompmartin, A, Watanabe, S, Vanwijck, R and Vikkula, M (2003) Capillary malformation-arteriovenous malformation, a new clinical and genetic disorder caused by RASA1 mutations. American Journal of Human Genetics 73, 1240–1249.Google Scholar
87.Hart, TC, Zhang, Y, Gorry, MC, Hart, PS, Cooper, M, Marazita, ML, Marks, JM, Cortelli, JR and Pallos, D (2002) A mutation in the SOS1 gene causes hereditary gingival fibromatosis type 1. American Journal of Human Genetics 70, 943–954.Google Scholar
88.Temtamy, SA, Miller, JD, Dorst, JP, Hussels-Maumenee, I, Salinas, C, Lacassie, Y and Kenyon, KR (1975) The Coffin-Lowry syndrome: a simply inherited trait comprising mental retardation, faciodigital anomalies and skeletal involvement. Birth Defects Original Article Series 11, 133–152.Google Scholar
89.Trivier, E, De Cesare, D, Jacquot, S, Pannetier, S, Zackai, E, Young, I, Mandel, JL, Sassone-Corsi, P and Hanauer, A (1996) Mutations in the kinase Rsk-2 associated with Coffin-Lowry syndrome. Nature 384, 567–570.Google Scholar
90.Nikopensius, T, Saag, M, Jagomagi, T, Annilo, T, Kals, M, Kivistik, PA, Milani, L and Metspalu, A (2013) A missense mutation in DUSP6 is associated with class III malocclusion. Journal of Dental Research 92, 893–898.Google Scholar
91.Li, Y, Liu, J, Hudson, M, Kim, S and Hatch, NE (2010) FGF2 promotes Msx2 stimulated PC-1 expression via Frs2/MAPK signaling. Journal of Cellular Biochemistry 111, 1346–1358.Google Scholar
92.Thouverey, C, Bechkoff, G, Pikula, S and Buchet, R (2009) Inorganic pyrophosphate as a regulator of hydroxyapatite or calcium pyrophosphate dihydrate mineral deposition by matrix vesicles. Osteoarthritis and Cartilage/OARS, Osteoarthritis Research Society 17, 64–72.Google Scholar
93.Terkeltaub, RA (2001) Inorganic pyrophosphate generation and disposition in pathophysiology. American Journal of Physiology. Cell Physiology 281, C1–C11.Google Scholar
94.Hessle, L, Johnson, KA, Anderson, HC, Narisawa, S, Sali, A, Goding, JW, Terkeltaub, R and Millan, JL (2002) Tissue-nonspecific alkaline phosphatase and plasma cell membrane glycoprotein-1 are central antagonistic regulators of bone mineralization. Proceedings of the National Academy of Sciences of the USA 99, 9445–9449.Google Scholar
95.Kim, HJ, Lee, MH, Park, HS, Park, MH, Lee, SW, Kim, SY, Choi, JY, Shin, HI and Ryoo, HM (2003) Erk pathway and activator protein 1 play crucial roles in FGF2-stimulated premature cranial suture closure. Developmental Dynamics 227, 335–346.Google Scholar
96.Byun, MR, Kim, AR, Hwang, JH, Kim, KM, Hwang, ES and Hong, JH (2014) FGF2 stimulates osteogenic differentiation through ERK induced TAZ expression. Bone 58, 72–80.Google Scholar
97.Quarto, N, Senarath-Yapa, K, Renda, A and Longaker, MT (2015) TWIST1 silencing enhances in vitro and in vivo osteogenic differentiation of human adipose-derived stem cells by triggering activation of BMP-ERK/FGF signaling and TAZ upregulation. Stem Cells 33, 833–847.Google Scholar
98.Rice, DP, Aberg, T, Chan, Y, Tang, Z, Kettunen, PJ, Pakarinen, L, Maxson, RE and Thesleff, I (2000) Integration of FGF and TWIST in calvarial bone and suture development. Development 127, 1845–1855.Google Scholar
99.Mansukhani, A, Bellosta, P, Sahni, M and Basilico, C (2000) Signaling by fibroblast growth factors (FGF) and fibroblast growth factor receptor 2 (FGFR2)-activating mutations blocks mineralization and induces apoptosis in osteoblasts. Journal of Cell Biology 149, 1297–1308.Google Scholar
100.Liu, J, Kwon, TG, Nam, HK and Hatch, NE (2013) Craniosynostosis-associated Fgfr2(C342Y) mutant bone marrow stromal cells exhibit cell autonomous abnormalities in osteoblast differentiation and bone formation. Biomed Research International 2013, 292506.Google Scholar
101.Kono, SJ, Oshima, Y, Hoshi, K, Bonewald, LF, Oda, H, Nakamura, K, Kawaguchi, H and Tanaka, S (2007) Erk pathways negatively regulate matrix mineralization. Bone 40, 68–74.Google Scholar
102.Thesleff, I (2003) Epithelial-mesenchymal signalling regulating tooth morphogenesis. Journal of Cell Science 116, 1647–1648.Google Scholar
103.Thesleff, I and Sharpe, P (1997) Signalling networks regulating dental development. Mechanisms of Development 67, 111–123.Google Scholar
104.Klein, OD, Minowada, G, Peterkova, R, Kangas, A, Yu, BD, Lesot, H, Peterka, M, Jernvall, J and Martin, GR (2006) Sprouty genes control diastema tooth development via bidirectional antagonism of epithelial-mesenchymal FGF signaling. Developmental Cell 11, 181–190.Google Scholar
105.Cho, KW, Cai, J, Kim, HY, Hosoya, A, Ohshima, H, Choi, KY and Jung, HS (2009) ERK activation is involved in tooth development via FGF10 signaling. Journal of Experimental Zoology. Part B, Molecular and Developmental Evolution 312, 901–911.Google Scholar
106.Lee, MJ, Cai, J, Kwak, SW, Cho, SW, Harada, H and Jung, HS (2009) MAPK mediates Hsp25 signaling in incisor development. Histochemistry and Cell Biology 131, 593–603.Google Scholar
107.Akram, A, McKnight, MM, Bellardie, H, Beale, V and Evans, RD (2015) Craniofacial malformations and the orthodontist. British Dental Journal 218, 129–141.Google Scholar
108.Cao, H, Alrejaye, N, Klein, OD, Goodwin, AF and Oberoi, S (2017) A review of craniofacial and dental findings of the RASopathies. Orthodontics & Craniofacial Research 20(Suppl 1), 32–38.Google Scholar
109.Goodwin, AF, Oberoi, S, Landan, M, Charles, C, Massie, JC, Fairley, C, Rauen, KA and Klein, OD (2014) Craniofacial and dental development in Costello syndrome. American Journal of Medical Genetics. Part A 164A, 1425–1430.Google Scholar
110.Goodwin, AF, Tidyman, WE, Jheon, AH, Sharir, A, Zheng, X, Charles, C, Fagin, JA, McMahon, M, Diekwisch, TG, Ganss, B, Rauen, KA and Klein, OD (2014) Abnormal Ras signaling in Costello syndrome (CS) negatively regulates enamel formation. Human Molecular Genetics 23, 682–692.Google Scholar
111.Goodwin, AF, Oberoi, S, Landan, M, Charles, C, Groth, J, Martinez, A, Fairley, C, Weiss, LA, Tidyman, WE, Klein, OD and Rauen, KA (2013) Craniofacial and dental development in cardio-facio-cutaneous syndrome: the importance of Ras signaling homeostasis. Clinical Genetics 83, 539–544.Google Scholar
112.Lu, C, Huguley, S, Cui, C, Cabaniss, LB, Waite, PD, Sarver, DM, Mamaeva, OA and MacDougall, M (2016) Effects of FGFR signaling on cell proliferation and differentiation of Apert dental cells. Cells Tissues Organs 201, 26–37.Google Scholar
113.Marangoni, P, Charles, C, Tafforeau, P, Laugel-Haushalter, V, Joo, A, Bloch-Zupan, A, Klein, OD and Viriot, L (2015) Phenotypic and evolutionary implications of modulating the ERK-MAPK cascade using the dentition as a model. Scientific Reports 5, 11658.Google Scholar
114.Abe, K, Miyoshi, K, Muto, T, Ruspita, I, Horiguchi, T, Nagata, T and Noma, T (2007) Establishment and characterization of rat dental epithelial derived ameloblast-lineage clones. Journal of Bioscience and Bioengineering 103, 479–485.Google Scholar
115.Sagomonyants, K and Mina, M (2014) Stage-specific effects of fibroblast growth factor 2 on the differentiation of dental pulp cells. Cells Tissues Organs 199, 311–328.Google Scholar
116.Sagomonyants, K, Kalajzic, I, Maye, P and Mina, M (2017) FGF signaling prevents the terminal differentiation of odontoblasts. Journal of Dental Research 96, 663–670.Google Scholar
117.Sagomonyants, K, Kalajzic, I, Maye, P and Mina, M (2015) Enhanced dentinogenesis of pulp progenitors by early exposure to FGF2. Journal of Dental Research 94, 1582–1590.Google Scholar
118.Eapen, A, Ramachandran, A and George, A (2012) Dentin phosphoprotein (DPP) activates integrin-mediated anchorage-dependent signals in undifferentiated mesenchymal cells. Journal of Biological Chemistry 287, 5211–5224.Google Scholar
119.Mizumachi, H, Yoshida, S, Tomokiyo, A, Hasegawa, D, Hamano, S, Yuda, A, Sugii, H, Serita, S, Mitarai, H, Koori, K, Wada, N and Maeda, H (2017) Calcium-sensing receptor-ERK signaling promotes odontoblastic differentiation of human dental pulp cells. Bone 101, 191–201.Google Scholar
120.Stokowski, A, Shi, S, Sun, T, Bartold, PM, Koblar, SA and Gronthos, S (2007) Ephb/ephrin-B interaction mediates adult stem cell attachment, spreading, and migration: implications for dental tissue repair. Stem Cells 25, 156–164.Google Scholar
121.Paula-Silva, FW, Ghosh, A, Arzate, H, Kapila, S, da Silva, LA and Kapila, YL (2010) Calcium hydroxide promotes cementogenesis and induces cementoblastic differentiation of mesenchymal periodontal ligament cells in a CEMP1- and ERK-dependent manner. Calcified Tissue International 87, 144–157.Google Scholar
122.Wang, J and Martin, JF (2017) Hippo pathway: an emerging regulator of craniofacial and dental development. Journal of Dental Research 96, 1229–1237.Google Scholar
123.Matsushita, K, Motani, R, Sakuta, T, Yamaguchi, N, Koga, T, Matsuo, K, Nagaoka, S, Abeyama, K, Maruyama, I and Torii, M (2000) The role of vascular endothelial growth factor in human dental pulp cells: induction of chemotaxis, proliferation, and differentiation and activation of the AP-1-dependent signaling pathway. Journal of Dental Research 79, 1596–1603.Google Scholar
124.Esnault, C, Gualdrini, F, Horswell, S, Kelly, G, Stewart, A, East, P, Matthews, N and Treisman, R (2017) ERK-Induced Activation of TCF family of SRF cofactors initiates a chromatin modification cascade associated with transcription. Molecular Cell 65, 1081–1095, e5.Google Scholar
125.Buchwalter, G, Gross, C and Wasylyk, B (2004) Ets ternary complex transcription factors. Gene 324, 1–14.Google Scholar
126.Dinsmore, CJ and Soriano, P (2018) MAPK and PI3K signaling: at the crossroads of neural crest development. Developmental Biology. https://doi.org/10.1016/j.ydbio.2018.02.003Google Scholar
127.Vitelli, F, Morishima, M, Taddei, I, Lindsay, EA and Baldini, A (2002) Tbx1 mutation causes multiple cardiovascular defects and disrupts neural crest and cranial nerve migratory pathways. Human Molecular Genetics 11, 915–922.Google Scholar
128.Trainor, P and Krumlauf, R (2000) Plasticity in mouse neural crest cells reveals a new patterning role for cranial mesoderm. Nature Cell Biology 2, 96–102.Google Scholar
129.Noden, DM and Trainor, PA (2005) Relations and interactions between cranial mesoderm and neural crest populations. Journal of Anatomy 207, 575–601.Google Scholar
130.Trumpp, A, Depew, MJ, Rubenstein, JL, Bishop, JM and Martin, GR (1999) Cre-mediated gene inactivation demonstrates that FGF8 is required for cell survival and patterning of the first branchial arch. Genes & Development 13, 3136–3148.Google Scholar
131.Tucker, AS, Yamada, G, Grigoriou, M, Pachnis, V and Sharpe, PT (1999) Fgf-8 determines rostral-caudal polarity in the first branchial arch. Development 126, 51–61.Google Scholar
132.Liu, W, Selever, J, Murali, D, Sun, X, Brugger, SM, Ma, L, Schwartz, RJ, Maxson, R, Furuta, Y and Martin, JF (2005) Threshold-specific requirements for Bmp4 in mandibular development. Developmental Biology 283, 282–293.Google Scholar
133.Tucker, AS, Matthews, KL and Sharpe, PT (1998) Transformation of tooth type induced by inhibition of BMP signaling. Science 282, 1136–1138.Google Scholar
134.Tucker, AS and Sharpe, PT (1999) Molecular genetics of tooth morphogenesis and patterning: the right shape in the right place. Journal of Dental Research 78, 826–834.Google Scholar
135.Chai, Y and Maxson, RE Jr. (2006) Recent advances in craniofacial morphogenesis. Developmental Dynamics 235, 2353–2375.Google Scholar
136.Nystrom, AM, Ekvall, S, Berglund, E, Bjorkqvist, M, Braathen, G, Duchen, K, Enell, H, Holmberg, E, Holmlund, U, Olsson-Engman, M, Anneren, G and Bondeson, ML (2008) Noonan and cardio-facio-cutaneous syndromes: two clinically and genetically overlapping disorders. Journal of Medical Genetics 45, 500–506.Google Scholar
137.Michailovici, I, Harrington, HA, Azogui, HH, Yahalom-Ronen, Y, Plotnikov, A, Ching, S, Stumpf, MP, Klein, OD, Seger, R and Tzahor, E (2014) Nuclear to cytoplasmic shuttling of ERK promotes differentiation of muscle stem/progenitor cells. Development 141, 2611–2620.Google Scholar
138.Michailovici, I, Eigler, T and Tzahor, E (2015) Craniofacial muscle development. Current Topics in Developmental Biology 115, 3–30.Google Scholar
139.Garcia-Gomez, R, Bustelo, XR and Crespo, P (2018) Protein-protein interactions: emerging oncotargets in the RAS-ERK pathway. Trends in Cancer 4, 616–633.Google Scholar
140.Wilkie, AO (2007) Cancer drugs to treat birth defects. Nature Genetics 39, 1057–1059.Google Scholar
141.Patel, AL and Shvartsman, SY (2018) Outstanding questions in developmental ERK signaling. Development 145. https://doi.org/10.1242/dev.143818Google Scholar
142.Guo, X and Wang, XF (2009) Signaling cross-talk between TGF-beta/BMP and other pathways. Cell Research 19, 71–88.Google Scholar
143.Rahman, MS, Akhtar, N, Jamil, HM, Banik, RS and Asaduzzaman, SM (2015) TGF-beta/BMP signaling and other molecular events: regulation of osteoblastogenesis and bone formation. Bone Research 3, 15005.Google Scholar
144.Cervenka, I, Wolf, J, Masek, J, Krejci, P, Wilcox, WR, Kozubik, A, Schulte, G, Gutkind, JS and Bryja, V (2011) Mitogen-activated protein kinases promote WNT/beta-catenin signaling via phosphorylation of LRP6. Molecular and Cellular Biology 31, 179–189.Google Scholar
145.Mao, JJ and Prockop, DJ (2012) Stem cells in the face: tooth regeneration and beyond. Cell Stem Cell 11, 291–301.Google Scholar
146.Zhao, H, Feng, J, Ho, TV, Grimes, W, Urata, M and Chai, Y (2015) The suture provides a niche for mesenchymal stem cells of craniofacial bones. Nature Cell Biology 17, 386–396.Google Scholar
147.Xu, Y, Malladi, P, Chiou, M and Longaker, MT (2007) Isolation and characterization of posterofrontal/sagittal suture mesenchymal cells in vitro. Plastic and Reconstructive Surgery 119, 819–829.Google Scholar
148.Maruyama, T, Jeong, J, Sheu, TJ and Hsu, W (2016) Stem cells of the suture mesenchyme in craniofacial bone development, repair and regeneration. Nature Communications 7, 10526.Google Scholar
149.Dutta, D, Heo, I and Clevers, H (2017) Disease modeling in stem cell-derived 3D organoid systems. Trends in Molecular Medicine 23, 393–410.Google Scholar
150.Athanassiou-Papaefthymiou, M, Papagerakis, P and Papagerakis, S (2015) Isolation and characterization of human adult epithelial stem cells from the periodontal ligament. Journal of Dental Research 94, 1591–1600.Google Scholar