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2 Roles of the BMP family in pattern formation of the vertebrate limb Naoyuki Wada 1, Tsutomu Nohno 1, Sumihare Noji 2 1 Department of Molecular Biology, Kawasaki Medical School, 577 Matsushima, Kurashiki, , Japan 2 Department of Biological Science and Technology, Faculty of Engineering, University of Tokushima, Minami-Jyosanjima, Tokushima, , Japan Summary In the process of limb development, various signaling molecules are produced in the organizing center of the limb bud. These molecules regulate pattern formation and the morphogenesis of the limb. Members of the BMP family and their receptors are expressed in the limb bud in spatiotemporal specific patterns. BMP signaling regulates chondrogenesis of limb mesenchyme, and promotes apoptosis of the interdigital soft tissue. Recently, this signaling was found to be involved in establishment of dorsoventral polarity of the limb bud and in regulation of limb growth via maintenance of the apical ectodermal ridge. BMPs also regulate digit morphology. In these events, BMPs work together with other signaling molecules, but they sometimes act as negative regulators of these other molecules so that limb morphogenesis can proceed normally. 2

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8 3. Niswander L: Pattern formation: old models out on a limb. Nature Rev Genet 4, (2003). 4. Tickle C: Patterning systems- From one end of the limb to the other. Dev Cell 4, (2003). 5. Tickle C, Munsterberg A: Vertebrate limb development- the early stages in chick and mouse. Curr Opin Genet & Dev 11, (2001). 6. Pizette S, Abate-Shen C, Niswander L: BMP controls proximodistal outgrowth, via induction of the apical ectodermal ridge, and dorsoventral patterning in the vertebrate limb. Development 128, (2001). 7. Ahn K, Mishina Y, Hanks MC, et al.: BMPR-IA signaling is required for the formation of the apical ectodermal ridge and dorsal-ventral patterning of the limb. Development 128, (2001). 8. Selevera J, Liua W, Lu M-F, et al.: Bmp4 in limb bud mesoderm regulates digit pattern by controlling AER development. Dev Biol 276, (2004). 9. Soshnikova N, Zechner D, Huelsken J, et al.: Genetic interaction between Wnt/b-catenin and BMP receptor signaling during formation of the AER and the dorsal-ventral axis in the limb. Genes & Dev 17, (2003). 10. Zhang Z, Yu X, Zhang Y, et al.: Targeted misexpression of constitutive active BMP receptor-ib causes bifurcation, duplication, and posterior transformation of digit in mouse limb. Dev Biol 220, (2000). 11. Barrow JR, Thomas KR, Boussadia-Zahui O, et al.: Ectodermal Wnt3/b-catenin signaling is required for the establishment and maintenance of the apical ectodermal ridge. Genes & Dev 17, (2003). 12. Pizette S, Niswander L: BMPs negatively regulate structure and function of the limb apical ectodermal ridge. Development 126, (1999). 13. Scherz PJ, Harfe BD, McMahon AP, Tabin CJ: The limb bud Shh-Fgf feedback loop is terminated by expansion of former ZPA cells. Science 305, (2004). 14. Sanz-Ezquerro JJ, Tickle C: Fgf signaling controls the number of Phalanges and tip formation in developing digits. Curr Biol 13, (2003). 15. Wilkie AOM, Oldridge M, Tang Z, Maxson Jr RE: Craniosynostosis and related limb anomalies. In Novartis Foundation Symposium 232, The molecular basis of 8

9 skeletogenesis. Wiley 2001, Drossopoulou G, Lewis KE, Sanz-Ezquerro JJ, et al.: A model for anteroposterior patterning of the vertebrate limb based on sequential long- and short-range Shh signaling and Bmp signaling. Development 127, (2000). 17. Dahn, RD and Fallon, JF : Interdigital regulation of digit identity and homeotic transformation by modulated BMP signaling. Science 289, (2000). 18. Merino R, Ganan Y, Macias D, et al.: Morphogenesis of digits in the avian limb is controlled by FGFs, TGFβs, and Noggin through BMP signaling. Dev Biol 200, (1998). 19. Ganan Y, Macias D, Basco RD, et al.: Morphological diversity of the avian foot is related with the pattern of msx gene expression in the developing autopod. Dev Biol 196, (1998). 20. Merino R, Rodriguez-Leon J, Macias D, et al.: The BMP antagonist Gremlin regulates outgrowth, chondrogenesis and programmed cell death in the developing limb. Development 126, (1999). 9

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Society of Evolutionary Studies, JapanNews Vol. 1, No. 2 1 C O N T E N T S 13 18 22 24 26 27 31 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 1Gibson-Brown J. J., Agulnik S. I., Silver L. M., Niswander L.,