Pleiotropic Patterning Response to Activation of Shh Signaling in the Limb Apical Ectodermal Ridge

Overview

Journal Dev Dyn

Publisher Wiley

Specialty Anatomy & Histology

Date 2011 Apr 6

PMID 21465622

Authors

Chi-Kuang Leo Wang

Mizuyo H Tsugane

Victoria Scranton

Robert A Kosher

Louis J Pierro

William B Upholt

Caroline N Dealy

Affiliations

Soon will be listed here.

Abstract

Sonic hedgehog (Shh) signaling in the limb plays a central role in coordination of limb patterning and outgrowth. Shh expression in the limb is limited to the cells of the zone of polarizing activity (ZPA), located in posterior limb bud mesoderm. Shh is not expressed by limb ectoderm or apical ectodermal ridge (AER), but recent studies suggest a role for AER-Shh signaling in limb patterning. Here, we have examined the effects of activation of Shh signaling in the AER. We find that targeted expression of Shh in the AER activates constitutive Shh signaling throughout the AER and subjacent limb mesoderm, and causes a range of limb patterning defects with progressive severity from mild polydactyly, to polysyndactyly with proximal defects, to severe oligodactyly with phocomelia and partial limb ventralization. Our studies emphasize the importance of control of the timing, level and location of Shh pathway signaling for limb anterior-posterior, proximal-distal, and dorsal-ventral patterning.

References

Benazet J, Zeller R . Vertebrate limb development: moving from classical morphogen gradients to an integrated 4-dimensional patterning system. Cold Spring Harb Perspect Biol. 2010; 1(4):a001339. PMC: 2773624. DOI: 10.1101/cshperspect.a001339. View

Goodrich L, Milenkovic L, Higgins K, Scott M . Altered neural cell fates and medulloblastoma in mouse patched mutants. Science. 1997; 277(5329):1109-13. DOI: 10.1126/science.277.5329.1109. View

Zuniga A, Haramis A, McMahon A, Zeller R . Signal relay by BMP antagonism controls the SHH/FGF4 feedback loop in vertebrate limb buds. Nature. 1999; 401(6753):598-602. DOI: 10.1038/44157. View

Butterfield N, Metzis V, McGlinn E, Bruce S, Wainwright B, Wicking C . Patched 1 is a crucial determinant of asymmetry and digit number in the vertebrate limb. Development. 2009; 136(20):3515-24. DOI: 10.1242/dev.037507. View

Cygan J, Johnson R, McMahon A . Novel regulatory interactions revealed by studies of murine limb pattern in Wnt-7a and En-1 mutants. Development. 1997; 124(24):5021-32. DOI: 10.1242/dev.124.24.5021. View

Coelho C, Upholt W, Kosher R . Role of the chicken homeobox-containing genes GHox-4.6 and GHox-8 in the specification of positional identities during the development of normal and polydactylous chick limb buds. Development. 1992; 115(2):629-37. DOI: 10.1242/dev.115.2.629. View

Yang Y, Niswander L . Interaction between the signaling molecules WNT7a and SHH during vertebrate limb development: dorsal signals regulate anteroposterior patterning. Cell. 1995; 80(6):939-47. DOI: 10.1016/0092-8674(95)90297-x. View

Butterfield N, McGlinn E, Wicking C . The molecular regulation of vertebrate limb patterning. Curr Top Dev Biol. 2010; 90:319-41. DOI: 10.1016/S0070-2153(10)90009-4. View

Scherz P, McGlinn E, Nissim S, Tabin C . Extended exposure to Sonic hedgehog is required for patterning the posterior digits of the vertebrate limb. Dev Biol. 2007; 308(2):343-54. PMC: 2100419. DOI: 10.1016/j.ydbio.2007.05.030. View

10.

Goodrich L, Johnson R, Milenkovic L, McMahon J, Scott M . Conservation of the hedgehog/patched signaling pathway from flies to mice: induction of a mouse patched gene by Hedgehog. Genes Dev. 1996; 10(3):301-12. DOI: 10.1101/gad.10.3.301. View

11.

Bastida M, Ros M . How do we get a perfect complement of digits?. Curr Opin Genet Dev. 2008; 18(4):374-80. DOI: 10.1016/j.gde.2008.06.009. View

12.

Delgado I, Dominguez-Frutos E, Schimmang T, Ros M . The incomplete inactivation of Fgf8 in the limb ectoderm affects the morphogenesis of the anterior autopod through BMP-mediated cell death. Dev Dyn. 2008; 237(3):649-58. DOI: 10.1002/dvdy.21452. View

13.

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

14.

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

15.

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

16.

Hill P, Gotz K, Ruther U . A SHH-independent regulation of Gli3 is a significant determinant of anteroposterior patterning of the limb bud. Dev Biol. 2009; 328(2):506-16. DOI: 10.1016/j.ydbio.2009.02.017. View

17.

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

18.

Pan Y, Liu Z, Shen J, Kopan R . Notch1 and 2 cooperate in limb ectoderm to receive an early Jagged2 signal regulating interdigital apoptosis. Dev Biol. 2005; 286(2):472-82. DOI: 10.1016/j.ydbio.2005.08.037. View

19.

Cameron D, Pennimpede T, Petkovich M . Tulp3 is a critical repressor of mouse hedgehog signaling. Dev Dyn. 2009; 238(5):1140-9. DOI: 10.1002/dvdy.21926. View

20.

Yang Y . Growth and patterning in the limb: signaling gradients make the decision. Sci Signal. 2009; 2(53):pe3. DOI: 10.1126/scisignal.253pe3. View