Abstract
Physiological cell death is a key mechanism that ensures appropriate development and maintenance of tissues and organs in multicellular organisms. Most structures in the vertebrate embryo exhibit defined areas of cell death at precise stages of development. In this regard the areas of interdigital cell death during limb development provide a paradigmatic model of massive cell death with an evident morphogenetic role in digit morphogenesis. Physiological cell death has been proposed to occur by apoptosis, cellular phenomena genetically controlled to orchestrate cell suicide following two main pathways, cytochrome C liberation from the mitochondria or activation of death receptors. Such pathways converge in the activation of cysteine proteases known as caspases, which execute the cell death program, leading to typical morphologic changes within the cell, termed apoptosis. According to these findings it would be expected that caspases loss of function experiments could cause inhibition of interdigital cell death promoting syndactyly phenotypes. A syndactyly phenotype is characterized by absence of digit freeing during development that, when caused by absence of interdigital cell death, is accompanied by the persistence of an interdigital membrane. However this situation has not been reported in any of the KO mice or chicken loss of function experiments ever performed. Moreover histological analysis of dying cells within the interdigit reveals the synchronic occurrence of different types of cell death. All these findings are indicative of caspase alternative and/or complementary mechanisms responsible for physiological interdigital cell death. Characterization of alternative cell death pathways is required to explain vertebrate morphogenesis. Today there is great interest in cell death via autophagy, which could substitute or act synergistically to the apoptotic pathway. Here we discuss what is known about physiological cell death in the developing interdigital tissue of vertebrate embryos, paying special attention to the avian species.
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References
Zakeri Z, Lockshin RA (2008) Cell death: history and future. Adv Exp Med Biol 615:1–11
Saunders JW Jr (1966) Death in embryonic systems. Science 154:604–612
Zuzarte-Luis V, Hurle JM (2005) Programmed cell death in the embryonic vertebrate limb. Semin Cell Dev Biol 16:261–269
Fernandez-Teran MA, Hinchliffe JR, Ros MA (2006) Birth and death of cells in limb development: a mapping study. Dev Dyn 235:2521–2537
Zuzarte-Luis V, Montero JA, Torre-Perez N, Garcia-Porrero JA, Hurle JM (2007) Cathepsin D gene expression outlines the areas of physiological cell death during embryonic development. Dev Dyn 236:880–885
Rodriguez-Guzman M, Montero JA, Santesteban E, Ganan Y, Macias D, Hurle JM (2007) Tendon-muscle crosstalk controls muscle bellies morphogenesis, which is mediated by cell death and retinoic acid signaling. Dev Biol 302:267–280
Mori C, Nakamura N, Kimura S, Irie H, Takigawa T, Shiota K (1995) Programmed cell death in the interdigital tissue of the fetal mouse limb is apoptosis with DNA fragmentation. Anat Rec 242:103–110
Hinchliffe JR, Ede DA (1973) Cell death and the development of limb form and skeletal pattern in normal and wingless (Ws) chick embryos. J Embryol Exp Morphol 30:753–772
Chen Y, Zhao X (1998) Shaping limbs by apoptosis. J Exp Zool 282:691–702
Bouldin CM, Harfe BD (2009) Aberrant FGF signaling, independent of ectopic hedgehog signaling, initiates preaxial polydactyly in dorking chickens. Dev Biol 334:133–141
Hurle JM, Colvee E, Fernandez-Teran MA (1985) Vascular regression during the formation of the free digits in the avian limb bud: a comparative study in chick and duck embryos. J Embryol Exp Morphol 85:239–250
Hurle JM, Fernandez-Teran MA (1983) Fine structure of the regressing interdigital membranes during the formation of the digits of the chick embryo leg bud. J Embryol Exp Morphol 78:195–209
Hurle JM, Fernandez-Teran MA (1984) Fine structure of the interdigital membranes during the morphogenesis of the digits of the webbed foot of the duck embryo. J Embryol Exp Morphol 79:201–210
Fallon JF, Cameron J (1977) Interdigital cell death during limb development of the turtle and lizard with an interpretation of evolutionary significance. J Embryol Exp Morphol 40:285–289
Salas-Vidal E, Valencia C, Covarrubias L (2001) Differential tissue growth and patterns of cell death in mouse limb autopod morphogenesis. Dev Dyn 220:295–306
Hernandez-Martinez R, Castro-Obregon S, Covarrubias L (2009) Progressive interdigital cell death: regulation by the antagonistic interaction between fibroblast growth factor 8 and retinoic acid. Development 136:3669–3678
Weatherbee SD, Behringer RR, Rasweiler JJ, Niswander LA (2006) Interdigital webbing retention in bat wings illustrates genetic changes underlying amniote limb diversification. Proc Natl Acad Sci USA 103:15103–15107
Ganan Y, Macias D, Basco RD, Merino R, Hurle JM (1998) Morphological diversity of the avian foot is related with the pattern of Msx gene expression in the developing autopod. Dev Biol 196:33–41
Cameron JA, Fallon JF (1977) The absence of cell death during development of free digits in amphibians. Dev Biol 55:331–338
Vlaskalin T, Wong CJ, Tsilfidis C (2004) Growth and apoptosis during larval forelimb development and adult forelimb regeneration in the newt (Notophthalmus Viridescens). Dev Genes Evol 214:423–431
Franssen RA, Marks S, Wake D, Shubin N (2005) Limb Chondrogenesis of the Seepage Salamander, Desmognathus Aeneus (Amphibia: Plethodontidae). J Morphol 265:87–101
Garcia-Martinez V, Macias D, Ganan Y, Garcia-Lobo JM, Francia MV, Fernandez-Teran MA, Hurle JM (1993) Internucleosomal DNA fragmentation and programmed cell death (Apoptosis) in the interdigital tissue of the embryonic chick leg bud. J Cell Sci 106(Pt 1):201–208
Wood W, Turmaine M, Weber R, Camp V, Maki RA, McKercher SR, Martin P (2000) Mesenchymal cells engulf and clear apoptotic footplate cells in macrophageless PU.1 null mouse embryos. Development 127:5245–5252
García-Martínez V, Climent V (1985) Apoptosis and necrosis in the areas of interdigital cell death of the developing chick embryo limb bud. An Desarr 29:119–129
Zuzarte-Luis V, Berciano MT, Lafarga M, Hurle JM (2006) Caspase redundancy and release of mitochondrial apoptotic factors characterize interdigital apoptosis. Apoptosis 11:701–715
Makarenkova H, Sugiura H, Yamagata K, Owens G (2005) Alternatively spliced variants of protocadherin 8 exhibit distinct patterns of expression during mouse development. Biochim Biophys Acta 1681:150–156
Hurle JM, Corson G, Daniels K, Reiter RS, Sakai LY, Solursh M (1994) Elastin exhibits a distinctive temporal and spatial pattern of distribution in the developing chick limb in association with the establishment of the cartilaginous skeleton. J Cell Sci 107(Pt 9):2623–2634
Dupe V, Ghyselinck NB, Thomazy V, Nagy L, Davies PJ, Chambon P, Mark M (1999) Essential roles of retinoic acid signaling in interdigital apoptosis and control of BMP-7 expression in mouse autopods. Dev Biol 208:30–43
McCulloch DR, Le Goff C, Bhatt S, Dixon LJ, Sandy JD, Apte SS (2009) Adamts5, the gene encoding a proteoglycan-degrading metalloprotease, is expressed by specific cell lineages during mouse embryonic development and in adult tissues. Gene Expr Patterns 9:314–323
McCulloch DR, Nelson CM, Dixon LJ, Silver DL, Wylie JD, Lindner V, Sasaki T, Cooley MA, Argraves WS, Apte SS (2009) ADAMTS metalloproteases generate active versican fragments that regulate interdigital web regression. Dev Cell 17:687–698
Miner JH, Cunningham J, Sanes JR (1998) Roles for laminin in embryogenesis: exencephaly, syndactyly, and placentopathy in mice lacking the laminin alpha5 chain. J Cell Biol 143:1713–1723
Arteaga-Solis E, Gayraud B, Lee SY, Shum L, Sakai L, Ramirez F (2001) Regulation of limb patterning by extracellular microfibrils. J Cell Biol 154:275–281
Debeer P, Schoenmakers EF, Twal WO, Argraves WS, De Smet L, Fryns JP, Van De Ven WJ (2002) The fibulin-1 gene (FBLN1) is disrupted in a t(12;22) associated with a complex type of synpolydactyly. J Med Genet 39:98–104
Smyth I, Du X, Taylor MS, Justice MJ, Beutler B, Jackson IJ (2004) The extracellular matrix gene frem1 is essential for the normal adhesion of the embryonic epidermis. Proc Natl Acad Sci USA 101:13560–13565
Bose K, Nischt R, Page A, Bader BL, Paulsson M, Smyth N (2006) Loss of nidogen-1 and -2 results in syndactyly and changes in limb development. J Biol Chem 281:39620–39629
Ramirez F, Sakai LY (2010) Biogenesis and Function of Fibrillin Assemblies. Cell Tissue Res 339:71–82
Lindsten T, Ross AJ, King A, Zong WX, Rathmell JC, Shiels HA, Ulrich E, Waymire KG, Mahar P, Frauwirth K et al (2000) The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues. Mol Cell 6:1389–1399
Hutcheson J, Scatizzi JC, Bickel E, Brown NJ, Bouillet P, Strasser A, Perlman H (2005) Combined loss of proapoptotic genes bak or bax with bim synergizes to cause defects in hematopoiesis and in thymocyte apoptosis. J Exp Med 201:1949–1960
Crocoll A, Herzer U, Ghyselinck NB, Chambon P, Cato AC (2002) Interdigital apoptosis and downregulation of BAG-1 expression in mouse autopods. Mech Dev 111:149–152
Nakanishi K, Maruyama M, Shibata T, Morishima N (2001) Identification of a caspase-9 substrate and detection of its cleavage in programmed cell death during mouse development. J Biol Chem 276:41237–41244
Chautan M, Chazal G, Cecconi F, Gruss P, Golstein P (1999) Interdigital cell death can occur through a necrotic and caspase-independent pathway. Curr Biol 9:967–970
Kuida K, Haydar TF, Kuan CY, Gu Y, Taya C, Karasuyama H, Su MS, Rakic P, Flavell RA (1998) Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9. Cell 94:325–337
Pop C, Salvesen GS (2009) Human caspases: activation, specificity, and regulation. J Biol Chem 284:21777–21781
Milligan CE, Prevette D, Yaginuma H, Homma S, Cardwell C, Fritz LC, Tomaselli KJ, Oppenheim RW, Schwartz LM (1995) Peptide inhibitors of the ICE protease family arrest programmed cell death of motoneurons in vivo and in vitro. Neuron 15:385–393
Kuida K, Zheng TS, Na S, Kuan C, Yang D, Karasuyama H, Rakic P, Flavell RA (1996) Decreased apoptosis in the brain and premature lethality in CPP32-deficient mice. Nature 384:368–372
Zheng TS, Hunot S, Kuida K, Flavell RA (1999) Caspase knockouts: matters of life and death. Cell Death Differ 6:1043–1053
Guo Y, Srinivasula SM, Druilhe A, Fernandes-Alnemri T, Alnemri ES (2002) Caspase-2 induces apoptosis by releasing proapoptotic proteins from mitochondria. J Biol Chem 277:13430–13437
Grossmann J, Walther K, Artinger M, Kiessling S, Scholmerich J (2001) Apoptotic signaling during initiation of detachment-induced apoptosis (“Anoikis”) of primary human intestinal epithelial cells. Cell Growth Differ 12:147–155
Bergeron L, Perez GI, Macdonald G, Shi L, Sun Y, Jurisicova A, Varmuza S, Latham KE, Flaws JA, Salter JC et al (1998) Defects in regulation of apoptosis in caspase-2-deficient mice. Genes Dev 12:1304–1314
Zuzarte-Luis V, Montero JA, Kawakami Y, Izpisua-Belmonte JC, Hurle JM (2007) Lysosomal cathepsins in embryonic programmed cell death. Dev Biol 301:205–217
Covarrubias L, Hernandez-Garcia D, Schnabel D, Salas-Vidal E, Castro-Obregon S (2008) Function of reactive oxygen species during animal development: passive or active? Dev Biol 320:1–11
Salas-Vidal E, Lomeli H, Castro-Obregon S, Cuervo R, Escalante-Alcalde D, Covarrubias L (1998) Reactive oxygen species participate in the control of mouse embryonic cell death. Exp Cell Res 238:136–147
Shan SW, Tang MK, Cai DQ, Chui YL, Chow PH, Grotewold L, Lee KK (2005) Comparative proteomic analysis identifies protein disulfide isomerase and peroxiredoxin 1 as new players involved in embryonic interdigital cell death. Dev Dyn 233:266–281
Schnabel D, Salas-Vidal E, Narvaez V, Sanchez-Carbente Mdel R, Hernandez-Garcia D, Cuervo R, Covarrubias L (2006) Expression and regulation of antioxidant enzymes in the developing limb support a function of ros in interdigital cell death. Dev Biol 291:291–299
Kirkland RA, Windelborn JA, Kasprzak JM, Franklin JL (2002) A bax-induced pro-oxidant state is critical for cytochrome c release during programmed neuronal death. J Neurosci 22:6480–6490
Leist M, Jaattela M (2001) Four deaths and a funeral: from caspases to alternative mechanisms. Nat Rev Mol Cell Biol 2:589–598
Li W, Yuan X, Nordgren G, Dalen H, Dubowchik GM, Firestone RA, Brunk UT (2000) Induction of cell death by the lysosomotropic detergent MSDH. FEBS Lett 470:35–39
Kirkegaard T, Jaattela M (2009) Lysosomal involvement in cell death and cancer. Biochim Biophys Acta 1793:746–754
Feldstein AE, Werneburg NW, Li Z, Bronk SF, Gores GJ (2006) Bax inhibition protects against free fatty acid-induced lysosomal permeabilization. Am J Physiol Gastrointest Liver Physiol 290:G1339–G1346
Castino R, Bellio N, Nicotra G, Follo C, Trincheri NF, Isidoro C (2007) Cathepsin D-bax death pathway in oxidative stressed neuroblastoma cells. Free Radic Biol Med 42:1305–1316
Boya P, Kroemer G (2008) Lysosomal membrane permeabilization in cell death. Oncogene 27:6434–6451
Boya P, Andreau K, Poncet D, Zamzami N, Perfettini JL, Metivier D, Ojcius DM, Jaattela M, Kroemer G (2003) Lysosomal membrane permeabilization induces cell death in a mitochondrion-dependent fashion. J Exp Med 197:1323–1334
Ishizaki Y, Jacobson MD, Raff MC (1998) A role for caspases in lens fiber differentiation. J Cell Biol 140:153–158
Saftig P, Hetman M, Schmahl W, Weber K, Heine L, Mossmann H, Koster A, Hess B, Evers M, von Figura K (1995) Mice deficient for the lysosomal proteinase cathepsin D exhibit progressive atrophy of the intestinal mucosa and profound destruction of lymphoid cells. EMBO J 14:3599–3608
Deussing J, Roth W, Saftig P, Peters C, Ploegh HL, Villadangos JA (1998) Cathepsins B and D are dispensable for major histocompatibility complex class II-mediated antigen presentation. Proc Natl Acad Sci USA 95:4516–4521
Roth W, Deussing J, Botchkarev VA, Pauly-Evers M, Saftig P, Hafner A, Schmidt P, Schmahl W, Scherer J, Anton-Lamprecht I et al (2000) Cathepsin L deficiency as molecular defect of furless: hyperproliferation of keratinocytes and pertubation of hair follicle cycling. FASEB J 14:2075–2086
Macias D, Ganan Y, Ros MA, Hurle JM (1996) In vivo inhibition of programmed cell death by local administration of FGF-2 and FGF-4 in the interdigital areas of the embryonic chick leg bud. Anat Embryol (Berl) 193:533–541
Wilkie AO, Patey SJ, Kan SH, van den Ouweland AM, Hamel BC (2002) FGFs, their receptors, and human limb malformations: clinical and molecular correlations. Am J Med Genet 112:266–278
Sun X, Mariani FV, Martin GR (2002) Functions of FGF signalling from the apical ectodermal ridge in limb development. Nature 418:501–508
Pajni-Underwood S, Wilson CP, Elder C, Mishina Y, Lewandoski M (2007) BMP signals control limb bud interdigital programmed cell death by regulating FGF signaling. Development 134:2359–2368
Mariani FV, Ahn CP, Martin GR (2008) Genetic evidence that FGFs have an instructive role in limb proximal-distal patterning. Nature 453:401–405
Montero JA, Ganan Y, Macias D, Rodriguez-Leon J, Sanz-Ezquerro JJ, Merino R, Chimal-Monroy J, Nieto MA, Hurle JM (2001) Role of FGFs in the control of programmed cell death during limb development. Development 128:2075–2084
Ota S, Zhou ZQ, Keene DR, Knoepfler P, Hurlin PJ (2007) Activities of N-Myc in the developing limb link control of skeletal size with digit separation. Development 134:1583–1592
Maatouk DM, Choi KS, Bouldin CM, Harfe BD (2009) In the limb AER Bmp2 and Bmp4 are required for dorsal-ventral patterning and interdigital cell death but not limb outgrowth. Dev Biol 327:516–523
Pizette S, Abate-Shen C, Niswander L (2001) BMP controls proximodistal outgrowth, via induction of the apical ectodermal ridge, and dorsoventral patterning in the vertebrate limb. Development 128:4463–4474
Bastida MF, Sheth R, Ros MA (2009) A BMP-Shh negative-feedback loop restricts Shh expression during limb development. Development 136:3779–3789
Macias D, Ganan Y, Sampath TK, Piedra ME, Ros MA, Hurle JM (1997) Role of BMP-2 and OP-1 (BMP-7) in programmed cell death and skeletogenesis during chick limb development. Development 124:1109–1117
Zou H, Wieser R, Massague J, Niswander L (1997) Distinct roles of type I bone morphogenetic protein receptors in the formation and differentiation of cartilage. Genes Dev 11:2191–2203
Merino R, Macias D, Ganan Y, Economides AN, Wang X, Wu Q, Stahl N, Sampath KT, Varona P, Hurle JM (1999) Expression and function of Gdf-5 during digit skeletogenesis in the embryonic chick leg bud. Dev Biol 206:33–45
Montero JA, Hurle JM (2007) Deconstructing digit chondrogenesis. Bioessays 29:725–737
Montero JA, Lorda-Diez CI, Ganan Y, Macias D, Hurle JM (2008) Activin/TGFbeta and BMP crosstalk determines digit chondrogenesis. Dev Biol 321:343–356
Francis-West PH, Robertson KE, Ede DA, Rodriguez C, Izpisua-Belmonte JC, Houston B, Burt DW, Gribbin C, Brickell PM, Tickle C (1995) Expression of genes encoding bone morphogenetic proteins and sonic hedgehog in talpid (ta3) limb buds: their relationships in the signalling cascade involved in limb patterning. Dev Dyn 203:187–197
Wang CK, Omi M, Ferrari D, Cheng HC, Lizarraga G, Chin HJ, Upholt WB, Dealy CN, Kosher RA (2004) Function of BMPs in the apical ectoderm of the developing mouse limb. Dev Biol 269:109–122
Geetha-Loganathan P, Nimmagadda S, Huang R, Scaal M, Christ B (2006) Expression pattern of BMPs during chick limb development. Anat Embryol (Berl) 211(Suppl 1):87–93
Zuzarte-Luis V, Montero JA, Rodriguez-Leon J, Merino R, Rodriguez-Rey JC, Hurle JM (2004) A new role for BMP5 during limb development acting through the synergic activation of Smad and MAPK pathways. Dev Biol 272:39–52
Merino R, Rodriguez-Leon J, Macias D, Ganan Y, Economides AN, Hurle JM (1999) The BMP antagonist gremlin regulates outgrowth, chondrogenesis and programmed cell death in the developing limb. Development 126:5515–5522
Yokouchi Y, Sakiyama J, Kameda T, Iba H, Suzuki A, Ueno N, Kuroiwa A (1996) BMP-2/-4 mediate programmed cell death in chicken limb buds. Development 122:3725–3734
Zou H, Niswander L (1996) Requirement for BMP signaling in interdigital apoptosis and scale formation. Science 272:738–741
Guha U, Gomes WA, Kobayashi T, Pestell RG, Kessler JA (2002) In vivo evidence that BMP signaling is necessary for apoptosis in the mouse limb. Dev Biol 249:108–120
Grotewold L, Plum M, Dildrop R, Peters T, Ruther U (2001) Bambi is coexpressed with Bmp-4 during mouse embryogenesis. Mech Dev 100:327–330
Vargesson N, Laufer E (2009) Negative Smad expression and regulation in the developing chick limb. PLoS One 4:e5173
Ross SA, McCaffery PJ, Drager UC, De Luca LM (2000) Retinoids in embryonal development. Physiol Rev 80:1021–1054
Mercader N, Leonardo E, Piedra ME, Martinez-A C, Ros MA, Torres M (2000) Opposing RA and FGF signals control proximodistal vertebrate limb development through regulation of Meis genes. Development 127:3961–3970
Zhao X, Sirbu IO, Mic FA, Molotkova N, Molotkov A, Kumar S, Duester G (2009) Retinoic acid promotes limb induction through effects on body axis extension but is unnecessary for limb patterning. Curr Biol 19:1050–1057
Dolle P, Ruberte E, Kastner P, Petkovich M, Stoner CM, Gudas LJ, Chambon P (1989) Differential expression of genes encoding alpha, beta and gamma retinoic acid receptors and CRABP in the developing limbs of the mouse. Nature 342:702–705
Kuss P, Villavicencio-Lorini P, Witte F, Klose J, Albrecht AN, Seemann P, Hecht J, Mundlos S (2009) Mutant Hoxd13 induces extra digits in a mouse model of synpolydactyly directly and by decreasing retinoic acid synthesis. J Clin Invest 119:146–156
Rodriguez-Leon J, Merino R, Macias D, Ganan Y, Santesteban E, Hurle JM (1999) Retinoic acid regulates programmed cell death through BMP signalling. Nat Cell Biol 1:125–126
Ahuja HS, James W, Zakeri Z (1997) Rescue of the limb deformity in hammertoe mutant mice by retinoic acid-induced cell death. Dev Dyn 208:466–481
Yashiro K, Zhao X, Uehara M, Yamashita K, Nishijima M, Nishino J, Saijoh Y, Sakai Y, Hamada H (2004) Regulation of retinoic acid distribution is required for proximodistal patterning and outgrowth of the developing mouse limb. Dev Cell 6:411–422
Francis JC, Radtke F, Logan MP (2005) Notch1 signals through Jagged2 to regulate apoptosis in the apical ectodermal ridge of the developing limb bud. Dev Dyn 234:1006–1015
Sidow A, Bulotsky MS, Kerrebrock AW, Bronson RT, Daly MJ, Reeve MP, Hawkins TL, Birren BW, Jaenisch R, Lander ES (1997) Serrate2 is disrupted in the mouse limb-development mutant syndactylism. Nature 389:722–725
Jiang R, Lan Y, Chapman HD, Shawber C, Norton CR, Serreze DV, Weinmaster G, Gridley T (1998) Defects in limb, craniofacial, and thymic development in Jagged2 mutant mice. Genes Dev 12:1046–1057
Pan Y, Liu Z, Shen J, Kopan R (2005) Notch1 and 2 cooperate in limb ectoderm to receive an early Jagged2 signal regulating interdigital apoptosis. Dev Biol 286:472–482
Chimal-Monroy J, Montero JA, Ganan Y, Macias D, Garcia-Porrero JA, Hurle JM (2002) Comparative analysis of the expression and regulation of Wnt5a, Fz4, and Frzb1 during digit formation and in micromass cultures. Dev Dyn 224:314–320
Knobloch J, Ruther U (2008) Shedding light on an old mystery: thalidomide suppresses survival pathways to induce limb defects. Cell Cycle 7:1121–1127
Grotewold L, Ruther U (2002) The Wnt antagonist Dickkopf-1 is regulated by Bmp signaling and c-Jun and modulates programmed cell death. EMBO J 21:966–975
Mukhopadhyay M, Shtrom S, Rodriguez-Esteban C, Chen L, Tsukui T, Gomer L, Dorward DW, Glinka A, Grinberg A, Huang SP et al (2001) Dickkopf1 is required for embryonic head induction and limb morphogenesis in the mouse. Dev Cell 1:423–434
Grotewold L, Ruther U (2002) Bmp, Fgf and Wnt signalling in programmed cell death and chondrogenesis during vertebrate limb development: the role of Dickkopf-1. Int J Dev Biol 46:943–947
Johnson EB, Hammer RE, Herz J (2005) Abnormal development of the apical ectodermal ridge and polysyndactyly in Megf7-deficient mice. Hum Mol Genet 14:3523–3538
Morello R, Bertin TK, Schlaubitz S, Shaw CA, Kakuru S, Munivez E, Hermanns P, Chen Y, Zabel B, Lee B (2008) Brachy-syndactyly caused by loss of Sfrp2 function. J Cell Physiol 217:127–137
Garcia-Moreno B (2009) Adaptations of proteins to cellular and subcellular pH. J Biol 8:98
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Thanks are due to Montse Fernandez-Calderón and Sonia Pérez-Mantecón for excellent technical support. JAM and JMH work is supported respectively by grants BFU2005-04393 and BFU2008-03930 from the Spanish Sciences and Innovation Ministry.
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Montero, J.A., Hurlé, J.M. Sculpturing digit shape by cell death. Apoptosis 15, 365–375 (2010). https://doi.org/10.1007/s10495-009-0444-5
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DOI: https://doi.org/10.1007/s10495-009-0444-5