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CLC number: R321.5

On-line Access: 2020-10-12

Received: 2020-05-31

Revision Accepted: 2020-08-06

Crosschecked: 2020-09-08

Cited: 0

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Citations:  Bibtex RefMan EndNote GB/T7714


Lan Zhang


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Journal of Zhejiang University SCIENCE B 2020 Vol.21 No.10 P.757-766


Apical ectodermal ridge regulates three principal axes of the developing limb

Author(s):  Guo-hao Lin, Lan Zhang

Affiliation(s):  Centre for Anatomy and Human Identification, University of Dundee, Dundee DD1 5EH, UK; more

Corresponding email(s):   zhanglan@sdpei.edu.cn

Key Words:  Apical ectodermal ridge (AER), Limb development, Fibroblast growth factor (FGF), Zone of polarizing activity (ZPA)

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Guo-hao Lin, Lan Zhang. Apical ectodermal ridge regulates three principal axes of the developing limb[J]. Journal of Zhejiang University Science B, 2020, 21(10): 757-766.

@article{title="Apical ectodermal ridge regulates three principal axes of the developing limb",
author="Guo-hao Lin, Lan Zhang",
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publisher="Zhejiang University Press & Springer",

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%T Apical ectodermal ridge regulates three principal axes of the developing limb
%A Guo-hao Lin
%A Lan Zhang
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%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B2000285

T1 - Apical ectodermal ridge regulates three principal axes of the developing limb
A1 - Guo-hao Lin
A1 - Lan Zhang
J0 - Journal of Zhejiang University Science B
VL - 21
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SP - 757
EP - 766
%@ 1673-1581
Y1 - 2020
PB - Zhejiang University Press & Springer
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DOI - 10.1631/jzus.B2000285

Understanding limb development not only gives insights into the outgrowth and differentiation of the limb, but also has clinical relevance. limb development begins with two paired limb buds (forelimb and hindlimb buds), which are initially undifferentiated mesenchymal cells tipped with a thickening of the ectoderm, termed the apical ectodermal ridge (AER). As a transitional embryonic structure, the AER undergoes four stages and contributes to multiple axes of limb development through the coordination of signalling centres, feedback loops, and other cell activities by secretory signalling and the activation of gene expression. Within the scope of proximodistal patterning, it is understood that while fibroblast growth factors (FGFs) function sequentially over time as primary components of the AER signalling process, there is still no consensus on models that would explain proximodistal patterning itself. In anteroposterior patterning, the AER has a dual-direction regulation by which it promotes the sonic hedgehog (Shh) gene expression in the zone of polarizing activity (ZPA) for proliferation, and inhibits Shh expression in the anterior mesenchyme. In dorsoventral patterning, the AER activates Engrailed-1 (En1) expression, and thus represses Wnt family member 7a (Wnt7a) expression in the ventral ectoderm by the expression of Fgfs, Sp6/8, and bone morphogenetic protein (Bmp) genes. The AER also plays a vital role in shaping the individual digits, since levels of Fgf4/8 and Bmps expressed in the AER affect digit patterning by controlling apoptosis. In summary, the knowledge of crosstalk within AER among the three main axes is essential to understand limb growth and pattern formation, as the development of its areas proceeds simultaneously.



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[1]Barrow JR, Thomas KR, Boussadia-Zahui O, et al., 2003. Ectodermal Wnt3/β-catenin signaling is required for the establishment and maintenance of the apical ectodermal ridge. Genes Dev, 17(3):394-409.

[2]Bouldin CM, Gritli-Linde A, Ahn S, et al., 2010. Shh pathway activation is present and required within the vertebrate limb bud apical ectodermal ridge for normal autopod patterning. Proc Natl Acad Sci USA, 107(12):5489-5494.

[3]Casanova JC, Uribe V, Badia-Careaga C, et al., 2011. Apical ectodermal ridge morphogenesis in limb development is controlled by Arid3b-mediated regulation of cell movements. Development, 138(6):1195-1205.

[4]Choi KS, Lee C, Maatouk DM, et al., 2012. Bmp2, Bmp4 and Bmp7 are co-required in the mouse AER for normal digit patterning but not limb outgrowth. PLoS ONE, 7(5):e37826.

[5]Cooper KL, Hu JKH, Ten Berge D, et al., 2011. Initiation of proximal-distal patterning in the vertebrate limb by signals and growth. Science, 332(6033):1083-1086.

[6]Danopoulos S, Parsa S, al Alam D, et al., 2013. Transient inhibition of FGFR2b-ligands signaling leads to irreversible loss of cellular β-catenin organization and signaling in AER during mouse limb development. PLoS ONE, 8(10):e76248.

[7]Delgado I, Torres M, 2017. Coordination of limb development by crosstalk among axial patterning pathways. Dev Biol, 429(2):382-386.

[8]Duboc V, Logan MPO, 2009. Building limb morphology through integration of signalling modules. Curr Opin Genet Dev, 19(5):497-503.

[9]Dudley AT, Ros MA, Tabin CJ, 2002. A re-examination of proximodistal patterning during vertebrate limb development. Nature, 418(6897):539-544.

[10]Fernandez-Teran M, Ros MA, 2008. The apical ectodermal ridge: morphological aspects and signaling pathways. Int J Dev Biol, 52(7):857-871.

[11]Gros J, Tabin CJ, 2014. Vertebrate limb bud formation is initiated by localized epithelial-to-mesenchymal transition. Science, 343(6176):1253-1256.

[12]Hajihosseini MK, Heath JK, 2002. Expression patterns of fibroblast growth factors-18 and -20 in mouse embryos is suggestive of novel roles in calvarial and limb development. Mech Dev, 113(1):79-83.

[13]Haro E, Delgado I, Junco M, et al., 2014. Sp6 and Sp8 transcription factors control AER formation and dorsal- ventral patterning in limb development. PLoS Genet, 10(8):e1004468.

[14]Irvine KD, Rauskolb C, 2001. Boundaries in development: formation and function. Annu Rev Cell Dev Biol, 17: 189-214.

[15]Itoh N, Ohta H, 2014. Fgf10: a paracrine-signaling molecule in development, disease, and regenerative medicine. Curr Mol Med, 14(4):504-509.

[16]Jin LB, Wu J, Bellusci S, et al., 2019. Fibroblast growth factor 10 and vertebrate limb development. Front Genet, 9:705.

[17]Kawakami Y, Capdevila J, Büscher D, et al., 2001. WNT signals control FGF-dependent limb initiation and AER induction in the chick embryo. Cell, 104(6):891-900.

[18]Laufer E, Nelson CE, Johnson RL, et al., 1994. Sonic hedgehog and Fgf-4 act through a signaling cascade and feedback loop to integrate growth and patterning of the developing limb bud. Cell, 79(6):993-1003.

[19]Lettice LA, Williamson I, Wiltshire JH, et al., 2012. Opposing functions of the ETS factor family define Shh spatial expression in limb buds and underlie polydactyly. Dev Cell, 22(2):459-467.

[20]Lewandoski M, Sun X, Martin GR, 2000. Fgf8 signalling from the AER is essential for normal limb development. Nat Genet, 26(4):460-463.

[21]Logan C, Hornbruch A, Campbell I, et al., 1997. The role of Engrailed in establishing the dorsoventral axis of the chick limb. Development, 124(12):2317-2324.

[22]Loomis CA, Harris E, Michaud J, et al., 1996. The mouse Engrailed-1 gene and ventral limb patterning. Nature, 382(6589):360-363.

[23]Mallick A, 2013. The function of apical ectodermal ridge in the formation of limb. Bangladesh J Sci Res, 26(1-2):95-99.

[24]Mariani FV, Ahn CP, Martin GR, 2008. Genetic evidence that FGFs have an instructive role in limb proximal–distal patterning. Nature, 453(7193):401-405.

[25]Martin GR, 1998. The roles of FGFs in the early development of vertebrate limbs. Genes Dev, 12(11):1571-1586.

[26]Mercader N, Leonardo E, Azpiazu N, et al., 1999. Conserved regulation of proximodistal limb axis development by Meis1/Hth. Nature, 402(6760):425-429.

[27]Mercader N, Leonardo E, Piedra ME, et al., 2000. Opposing RA and FGF signals control proximodistal vertebrate limb development through regulation of Meis genes. Development, 127(18):3961-3970.

[28]Mercader N, Selleri L, Criado LM, et al., 2009. Ectopic Meis1 expression in the mouse limb bud alters P-D patterning in a Pbx1-independent manner. Int J Dev Biol, 53(8-10):1483-1494.

[29]Moon AM, Capecchi MR, 2000. Fgf8 is required for outgrowth and patterning of the limbs. Nat Genet, 26(4):455-459.

[30]Moon AM, Boulet AM, Capecchi MR, 2000. Normal limb development in conditional mutants of Fgf4. Development, 127(5):989-996.

[31]Nelson CE, Morgan BA, Burke AC, et al., 1996. Analysis of Hox gene expression in the chick limb bud. Development, 122(5):1449-1466.

[32]Niederreither K, Fraulob V, Garnier JM, et al., 2002. Differential expression of retinoic acid-synthesizing (RALDH) enzymes during fetal development and organ differentiation in the mouse. Mech Dev, 110(1-2):165-171.

[33]Nishimoto S, Wilde SM, Wood S, et al., 2015. RA acts in a coherent feed-forward mechanism with Tbx5 to control limb bud induction and initiation. Cell Rep, 12(5):879-891.

[34]Niswander L, Martin GR, 1992. Fgf-4 expression during gastrulation, myogenesis, limb and tooth development in the mouse. Development, 114(3):755-768.

[35]Niswander L, Tickle C, Vogel A, et al., 1993. FGF-4 replaces the apical ectodermal ridge and directs outgrowth and patterning of the limb. Cell, 75(3):579-587.

[36]Niswander L, Jeffrey S, Martin GR, et al., 1994. A positive feedback loop coordinates growth and patterning in the vertebrate limb. Nature, 371(6498):609-612.

[37]Pajni-Underwood S, Wilson CP, Elder C, et al., 2007. BMP signals control limb bud interdigital programmed cell death by regulating FGF signaling. Development, 134(12):2359-2368.

[38]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(22):4463-4474.

[39]Pownall ME, Isaacs HV, 2010. FGF Signalling in Vertebrate Development. Morgan and Claypool Life Sciences, San Rafael, USA.

[40]Rodriguez-Esteban C, Tsukui T, Yonei S, et al., 1999. The T-box genes Tbx4 and Tbx5 regulate limb outgrowth and identity. Nature, 398(6730):814-818.

[41]Rodriguez-Leon J, Tomas AR, Johnson A, et al., 2013. Recent advances in the study of limb development: the emergence and function of the apical ectodermal ridge. In: Reyes D, Casales A (Eds.), Embryo Development: Stages, Mechanisms and Clinical Outcomes. Nova Science Publishers Inc., New York, p.77-112.

[42]Roselló-Díez A, Arques CG, Delgado I, et al., 2014. Diffusible signals and epigenetic timing cooperate in late proximo-distal limb patterning. Development, 141(7):1534-1543.

[43]Saunders JW Jr, 1948. The proximo‐distal sequence of origin of the parts of the chick wing and the role of the ectoderm. J Exp Zool, 108(3):363-403.

[44]Scherz PJ, Harfe BD, McMahon AP, et al., 2004. The limb bud Shh-Fgf feedback loop is terminated by expansion of former ZPA cells. Science, 305(5682):396-399.

[45]Sekine K, Ohuchi H, Fujiwara M, et al., 1999. Fgf10 is essential for limb and lung formation. Nat Genet, 21(1):138-141.

[46]Sheeba CJ, Logan MPO, 2017. The roles of T-box genes in vertebrate limb development. Curr Top Dev Biol, 122: 355-381.

[47]Summerbell D, Lewis JH, Wolpert L, 1973. Positional information in chick limb morphogenesis. Nature, 244(5417):492-496.

[48]Sun X, Lewandoski M, Meyers EN, et al., 2000. Conditional inactivation of Fgf4 reveals complexity of signalling during limb bud development. Nat Genet, 25(1):83-86.

[49]Sun X, Mariani FV, Martin GR, 2002. Functions of FGF signalling from the apical ectodermal ridge in limb development. Nature, 418(6897):501-508.

[50]Tabin C, Wolpert L, 2007. Rethinking the proximodistal axis of the vertebrate limb in the molecular era. Genes Dev, 21(12):1433-1442.

[51]Tickle C, 2003. Patterning systems—from one end of the limb to the other. Dev Cell, 4(4):449-458.

[52]Tickle C, Wolpert L, 2002. The progress zone—alive or dead? Nat Cell Biol, 4(9):E216-E217.

[53]Towers M, Tickle C, 2009. Growing models of vertebrate limb development. Development, 136(2):179-190.

[54]Wolpert L, 2002. Limb patterning: reports of model’s death exaggerated. Curr Biol, 12(18):R628-R630.

[55]Yashiro K, Zhao XL, Uehara M, et al., 2004. Regulation of retinoic acid distribution is required for proximodistal patterning and outgrowth of the developing mouse limb. Dev Cell, 6(3):411-422.

[56]Zeller R, López-Ríos J, Zuniga A, 2009. Vertebrate limb bud development: moving towards integrative analysis of organogenesis. Nat Rev Genet, 10(12):845-858.

[57]Zhang Z, Verheyden JM, Hassell JA, et al., 2009. FGF-regulated Etv genes are essential for repressing Shh expression in mouse limb buds. Dev Cell, 16(4):607-613.

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