FGF-regulated Etv Genes Are Essential for Repressing Shh Expression in Mouse Limb Buds

Overview

Journal Dev Cell

Publisher Cell Press

Specialties Cell Biology
Reproductive Medicine

Date 2009 Apr 24

PMID 19386269

Citations 87

Authors

Zhen Zhang

Jamie M Verheyden

John A Hassell

Xin Sun

Affiliations

Soon will be listed here.

Abstract

Anterior-posterior (A-P) patterning of the vertebrate limb is controlled by sonic hedgehog (SHH) signaling, and the precise restriction of Shh expression to the posterior limb bud is essential for its polarizing effect. Fibroblast growth factor (FGF) signaling, a key control of proximal-distal (P-D) limb outgrowth, is known to promote Shh expression in the posterior limb bud. Here, we show that conditional knockout of the FGF-activated transcription factor genes Etv4 and Etv5 in mouse led to ectopic Shh expression in the anterior limb bud and a preaxial polydactyly (PPD) skeletal phenotype. These unexpected results suggest that ETV4 and ETV5 act downstream of FGF signaling to inhibit Shh expression in the anterior limb bud. This finding elucidates a novel aspect of the mechanism coordinating limb development along the A-P and P-D axes.

Citing Articles

Evidence for Fgf and Wnt regulation of during limb development via two limb-specific -associated -regulatory modules.

Britton J, Somogyi-Leatigaga A, Watson B, Haro E, Mulder C, Kennedy K Front Cell Dev Biol. 2025; 13:1552716.

PMID: 40052149 PMC: 11882541. DOI: 10.3389/fcell.2025.1552716.

ETVs dictate hPSC differentiation by tuning biophysical properties.

Ziojla N, Socha M, Guerra M, Kizewska D, Blaszczyk K, Urbaniak E Nat Commun. 2025; 16(1):1999.

PMID: 40011454 PMC: 11865489. DOI: 10.1038/s41467-025-56591-6.

A dominant missense variant within LMBR1 related to equine polydactyly.

Luan Y, Zhong L, Li C, Yue X, Ye M, Wang J Commun Biol. 2024; 7(1):1420.

PMID: 39482424 PMC: 11527984. DOI: 10.1038/s42003-024-07065-w.

ETV4 and ETV5 Orchestrate FGF-Mediated Lineage Specification and Epiblast Maturation during Early Mouse Development.

Simon C, Garg V, Kuo Y, Niakan K, Hadjantonakis A bioRxiv. 2024; .

PMID: 39091858 PMC: 11291132. DOI: 10.1101/2024.07.24.604964.

Sensory nerve regulates progenitor cells via FGF-SHH axis in tooth root morphogenesis.

Pei F, Ma L, Guo T, Zhang M, Jing J, Wen Q Development. 2023; 151(2.

PMID: 38108472 PMC: 10820866. DOI: 10.1242/dev.202043.

References

Te Welscher P, Zuniga A, Kuijper S, Drenth T, Goedemans H, Meijlink F . Progression of vertebrate limb development through SHH-mediated counteraction of GLI3. Science. 2002; 298(5594):827-30. DOI: 10.1126/science.1075620. View

Riddle R, Johnson R, Laufer E, Tabin C . Sonic hedgehog mediates the polarizing activity of the ZPA. Cell. 1993; 75(7):1401-16. DOI: 10.1016/0092-8674(93)90626-2. View

Chiang C, Litingtung Y, Harris M, Simandl B, Li Y, Beachy P . Manifestation of the limb prepattern: limb development in the absence of sonic hedgehog function. Dev Biol. 2001; 236(2):421-35. DOI: 10.1006/dbio.2001.0346. View

Firulli B, Krawchuk D, Centonze V, Vargesson N, Virshup D, Conway S . Altered Twist1 and Hand2 dimerization is associated with Saethre-Chotzen syndrome and limb abnormalities. Nat Genet. 2005; 37(4):373-81. PMC: 2568820. DOI: 10.1038/ng1525. View

Litingtung Y, Dahn R, Li Y, Fallon J, Chiang C . Shh and Gli3 are dispensable for limb skeleton formation but regulate digit number and identity. Nature. 2002; 418(6901):979-83. DOI: 10.1038/nature01033. View

Lu P, Minowada G, Martin G . Increasing Fgf4 expression in the mouse limb bud causes polysyndactyly and rescues the skeletal defects that result from loss of Fgf8 function. Development. 2005; 133(1):33-42. DOI: 10.1242/dev.02172. View

Verheyden J, Lewandoski M, Deng C, Harfe B, Sun X . Conditional inactivation of Fgfr1 in mouse defines its role in limb bud establishment, outgrowth and digit patterning. Development. 2005; 132(19):4235-45. PMC: 6986394. DOI: 10.1242/dev.02001. View

Logan M, Martin J, Nagy A, Lobe C, Olson E, Tabin C . Expression of Cre Recombinase in the developing mouse limb bud driven by a Prxl enhancer. Genesis. 2002; 33(2):77-80. DOI: 10.1002/gene.10092. View

Laing M, Coonrod S, Hinton B, Downie J, Tozer R, Rudnicki M . Male sexual dysfunction in mice bearing targeted mutant alleles of the PEA3 ets gene. Mol Cell Biol. 2000; 20(24):9337-45. PMC: 102190. DOI: 10.1128/MCB.20.24.9337-9345.2000. View

10.

Sun X, Mariani F, Martin G . Functions of FGF signalling from the apical ectodermal ridge in limb development. Nature. 2002; 418(6897):501-8. DOI: 10.1038/nature00902. View

11.

Yu K, Ornitz D . FGF signaling regulates mesenchymal differentiation and skeletal patterning along the limb bud proximodistal axis. Development. 2007; 135(3):483-91. DOI: 10.1242/dev.013268. View

12.

Livet J, Sigrist M, Stroebel S, de Paola V, Price S, Henderson C . ETS gene Pea3 controls the central position and terminal arborization of specific motor neuron pools. Neuron. 2002; 35(5):877-92. DOI: 10.1016/s0896-6273(02)00863-2. View

13.

Mariani F, Martin G . Deciphering skeletal patterning: clues from the limb. Nature. 2003; 423(6937):319-25. DOI: 10.1038/nature01655. View

14.

Te Welscher P, Fernandez-Teran M, Ros M, Zeller R . Mutual genetic antagonism involving GLI3 and dHAND prepatterns the vertebrate limb bud mesenchyme prior to SHH signaling. Genes Dev. 2002; 16(4):421-6. PMC: 155343. DOI: 10.1101/gad.219202. View

15.

Laufer E, Nelson C, Johnson R, Morgan B, Tabin C . Sonic hedgehog and Fgf-4 act through a signaling cascade and feedback loop to integrate growth and patterning of the developing limb bud. Cell. 1994; 79(6):993-1003. DOI: 10.1016/0092-8674(94)90030-2. View

16.

McGlinn E, Tabin C . Mechanistic insight into how Shh patterns the vertebrate limb. Curr Opin Genet Dev. 2006; 16(4):426-32. DOI: 10.1016/j.gde.2006.06.013. View

17.

Zhu J, Nakamura E, Nguyen M, Bao X, Akiyama H, Mackem S . Uncoupling Sonic hedgehog control of pattern and expansion of the developing limb bud. Dev Cell. 2008; 14(4):624-32. PMC: 8284562. DOI: 10.1016/j.devcel.2008.01.008. View

18.

Sanz-Ezquerro J, Tickle C . Autoregulation of Shh expression and Shh induction of cell death suggest a mechanism for modulating polarising activity during chick limb development. Development. 2000; 127(22):4811-23. DOI: 10.1242/dev.127.22.4811. View

19.

Anderson R, Landry M, Reginelli A, Taylor G, Achkar C, Gudas L . Conversion of anterior limb bud cells to ZPA signaling cells in vitro and in vivo. Dev Biol. 1994; 164(1):241-57. DOI: 10.1006/dbio.1994.1195. View

20.

Towers M, Mahood R, Yin Y, Tickle C . Integration of growth and specification in chick wing digit-patterning. Nature. 2008; 452(7189):882-6. DOI: 10.1038/nature06718. View