Abstract
Digit identity determination is a longstanding question of developmental biology. Through recent embryological and molecular studies, molecular mechanisms that underlie the determination of morphological identity of the digits have been revealed to a certain extent. The first insight into the problem was provided by the discovery of the zone of polarizing activity (ZPA) and its responsible signaling molecule, sonic hedgehog (SHH). However, SHH signaling does not directly determine digit identity. We identified interdigit mesenchymes as the source of signals that activate SMAD1/5/8 in the phalanx-forming region (PFR) cells in a way reflecting the earlier SHH signaling. PFR is located immediately distal to the condensed cartilage of the digit primordium and serves as the zone of cartilage differentiation, and the differential strength of SMAD1/5/8 activation in the PFR was correlated with digit identity.
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References
Bandyopadhyay A, Tsuji K, Cox K, Harfe BD, Rosen V, Tabin CJ (2006) Genetic analysis of the roles of BMP2, BMP4, and BMP7 in limb patterning and skeletogenesis. PLoS Genet 2:e216
Baur ST, Mai JJ, Dymecki SM (2000) Combinatorial signaling through BMP receptor IB and GDF5: shaping of the distal mouse limb and the genetics of distal limb diversity. Development (Camb) 127:605–619
Dahn RD, Fallon JF (2000) Interdigit regulation of digit identity and homeotic transformation by modulated BMP signaling. Science 289:438–441
Dunn IC, Paton IR, Clelland AK, Sebastian S, Johnson EJ, McTeir L, Windsor D, Sherman A, Sang H, Burt DW, Tickle C, Davey MG (2011) The chicken polydactyly (Po) locus causes allelic imbalance and ectopic expression of Shh during limb development. Dev Dyn 240:1163–1172
Harfe BD, Scherz PJ, Nissim S, Tian H, McMahon AP, Tabin CJ (2004) Evidence for an expansion-based temporal Shh gradient in specifying vertebrate digit identities. Cell 118:517–528
Litingtung Y, Dahn RD, Li Y, Fallon JF, Chiang C (2002) Shh and Gli3 are dispensable for limb skeleton formation but regulate digit number and identity. Nature (Lond) 418:979–983
Merino R, Macias D, Gañan 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 206:2161–2170
Morgan BA, Izpisúa-Belmonte JC, Duboule D, Tabin CJ (1992) Targeted misexpression of Hox-4.6 in the avian limb bud causes apparent homeotic transformations. Nature 358:236–239
Riddle RD, Johnson RL, Laufer E, Tabin C (1993) Sonic hedgehog mediates the polarizing activity of the ZPA. Cell 75:1401–1416
Saunders JW Jr (1972) Developmental control of three-dimensional polarity in the avian limb. Ann N Y Acad Sci 25:29–42
Saunders JW Jr, Gasseling MT (1968) Ectodermal-mesenchymal interactions in the origin of limb symmetry. In: Fleischmajer R, Billingham RE (eds) Epithelial–mesenchymal interactions. William & Wilkins, Baltimore, pp 78–97
Scherz PJ, McGlinn E, Nissim S, Tabin CJ (2007) Extended exposure to Sonic hedgehog is required for patterning the posterior digits of the vertebrate limb. Dev Biol 308:343–354
Seemann P, Schwappacher R, Kjaer KW, Krakow D, Lehmann K, Dawson K, Stricker S, Pohl J, Plöger F, Staub E, Nickel J, Sebald W, Knaus P, Mundlos S (2005) Activating and deactivating mutations in the receptor interaction site of GDF5 cause symphalangism or brachydactyly type A2. J Clin Invest 115:2373–2381
Settle SH Jr, Rountree RB, Sinha A, Thacker A, Higgins K, Kingsley DM (2003) Multiple joint and skeletal patterning defects caused by single and double mutations in the mouse Gdf6 and Gdf5 genes. Dev Biol 254:116–130
Sheth R, Marcon L, Bastida MF, Junco M, Quintana L, Dahn R, Kmita M, Sharpe J, Ros MA (2012) Hox genes regulate digit patterning by controlling the wavelength of a Turing-type mechanism. Science 338:1476–1480
Suzuki T, Takeuchi J, Koshiba-Takeuchi K, Ogura T (2004) Tbx genes specify posterior digit identity through Shh and BMP signaling. Dev Cell 6:43–53
Suzuki T, Hasso SM, Fallon JF (2008) Unique SMAD1/5/8 activity at the phalanx-forming region determines digit identity. Proc Natl Acad Sci USA 105:4185–4190
Turing AM (1952) The chemical basis of morphogenesis. Phil Trans R Soc Lond B 237(641):37–72
Witte F, Chan D, Economides AN, Mundlos S, Stricker S (2010) Receptor tyrosine kinase-like orphan receptor 2 (ROR2) and Indian hedgehog regulate digit outgrowth mediated by the phalanx-forming region. Proc Natl Acad Sci USA 107:14211–14216
Yang Y, Drossopoulou G, Chuang PT, Duprez D, Marti E, Bumcrot D, Vargesson N, Clarke J, Niswander L, McMahon A, Tickle C (1997) Relationship between dose, distance and time in Sonic Hedgehog-mediated regulation of anteroposterior polarity in the chick limb. Development (Camb) 124:4393–4404
Yi SE, Daluiski A, Pederson R, Rosen V, Lyons KM (2000) The type I BMP receptor BMPRIB is required for chondrogenesis in the mouse limb. Development (Camb) 127:621–630
Zhu J, Nakamura E, Nguyen MT, Bao X, Akiyama H, Mackem S (2008) Uncoupling Sonic hedgehog control of pattern and expansion of the developing limb bud. Dev Cell 14:624–632
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Suzuki, T. (2014). Secondary Smad1/5/8-Dependent Signaling Downstream of SHH Determines Digit Identity. In: Kondoh, H., Kuroiwa, A. (eds) New Principles in Developmental Processes. Springer, Tokyo. https://doi.org/10.1007/978-4-431-54634-4_12
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DOI: https://doi.org/10.1007/978-4-431-54634-4_12
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