Manifestation of the limb prepattern: limb development in the absence of sonic hedgehog function.
Open accessAbstract
The secreted protein encoded by the Sonic hedgehog (Shh) gene is localized to the posterior margin of vertebrate limb buds and is thought to be a key signal in establishing anterior-posterior limb polarity. In the Shh(-/-) mutant mouse, the development of many embryonic structures, including the limb, is severely compromised. In this study, we report the analysis of Shh(-/-) mutant limbs in detail. Each mutant embryo has four limbs with recognizable humerus/femur bones that have anterior-posterior polarity. Distal to the elbow/knee joints, skeletal elements representing the zeugopod form but lack identifiable anterior-posterior polarity. Therefore, Shh specifically becomes necessary for normal limb development at or just distal to the stylopod/zeugopod junction (elbow/knee joints) during mouse limb development. The forelimb autopod is represented by a single distal cartilage element, while the hindlimb autopod is invariably composed of a single digit with well-formed interphalangeal joints and a dorsal nail bed at the terminal phalanx. Analysis of GDF5 and Hoxd11-13 expression in the hindlimb autopod suggests that the forming digit has a digit-one identity. This finding is corroborated by the formation of only two phalangeal elements which are unique to digit one on the foot. The apical ectodermal ridge (AER) is induced in the Shh(-/-) mutant buds with relatively normal morphology. We report that the architecture of the Shh(-/-) AER is gradually disrupted over developmental time in parallel with a reduction of Fgf8 expression in the ridge. Concomitantly, abnormal cell death in the Shh(-/-) limb bud occurs in the anterior mesenchyme of both fore- and hindlimb. It is notable that the AER changes and mesodermal cell death occur earlier in the Shh(-/-) forelimb than the hindlimb bud. This provides an explanation for the hindlimb-specific competence to form autopodial structures in the mutant. Finally, unlike the wild-type mouse limb bud, the Shh(-/-) mutant posterior limb bud mesoderm does not cause digit duplications when grafted to the anterior border of chick limb buds, and therefore lacks polarizing activity. We propose that a prepattern exists in the limb field for the three axes of the emerging limb bud as well as specific limb skeletal elements. According to this model, the limb bud signaling centers, including the zone of polarizing activity (ZPA) acting through Shh, are required to elaborate upon the axial information provided by the native limb field prepattern.
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Loss of AER function results in anterior-distal cell death and reduction of Shh activity in tetrapod limbs.
“This finding is similar to the effect of loss of AER function resulting in anterior-distal cell death and reduction of Shh activity in tetrapod limbs [37]–[39].”
From Zebrafish eda and edar Mutants Reveal Conserved and Ancestral Roles of Ectodysplasin Signaling in Vertebrates (2008) · cites this paper as [39]
The Discussion (page unavailable) says that chick limbless buds lack an AER, do not express Shh, and are eliminated by cell death. But it describes death of the entire bud, not specifically anterior-distal cells. The Cell Death and Proliferation section (page unavailable) locates anterior cell death in Shh-deficient mouse limbs; it does not show that loss of AER function caused that death or reduced Shh activity. (LLM, conf=0.84)
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Wang, B., Fallon, J. F., & Beachy, P. A. (2000) · Cell · doi:10.1016/s0092-8674(00)80678-9 · Cited by 1,014 · see citing works
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- Ros, M. A., Lopez-Martinez, A., Simandl, B. K., Rodriguez, C., Izpisua-Belmonte, J. C., Dahn, R., and Fallon, J. F. (1996b). Insights into gene expression associated with limb budding using a limbless mutant. In "5th International Limb Development and Regeneration Conference," York, U.K. Ros, M. A., Simandl, B. K., Clark, A. W., and Fallon, J. F. (2000). Methods for manipulating the chick limb bud to study gene expressions, tissue interactions and patterning. In "Development Biology Protocols" (R. S. Tuan and C. W. Lo, Eds.), pp 245-266.
- Rubin, L., and Saunders, J. J. (1972). Ectodermal-mesodermal inter- actions in the growth of limb buds in the chick embryo: Con- stancy and temporal limits of the ectodermal induction. Dev. Biol. 28, 94 -112.
- Za ´ka ´ny, J., Fromental-Ramin, C., Warot, X., and Duboule, D. (1997). Regulation of number and size of digits by posterior Hox genes: A dose-dependent mechanisms with potential evolution- ary implications. Proc. Natl. Acad. Sci. USA 94, 13695-13700.
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HES1 is a novel downstream modifier of the SHH-GLI3 Axis in the development of preaxial polydactyly
Sharma, D., Mirando, A. J., Leinroth, A., Long, J. T., Karner, C. M., & Hilton, M. J. (2021) · PLOS Genetics · doi:10.1371/journal.pgen.1009982 · Cited by 10 · see citing works
- Authors
- Chiang, C., Litingtung, Y., Harris, M. P., Simandl, B. K., Li, Y., Beachy, P. A., & Fallon, J. F.
- Affiliations
- Vanderbilt University Medical Center (US)
- University of Wisconsin–Madison (US)
- Johns Hopkins University (US)
- Corresponding author
- Chiang, Chin
- Fallon, John F.
- Venue
- Developmental Biology
- Publisher
- Elsevier BV
- Published
- 2001-08
- Volume
- 236
- Issue
- 2
- Pages
- 421-435
- ISSN
- 0012-1606 (ISSN-L)
- OpenAlex
- W2105505995
- Cited by
- 427
- References
- 1
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 5 · 2023: 5 · 2022: 11 · 2021: 12 · 2020: 9 · 2019: 7 · 2018: 11 · 2017: 16 · 2016: 18 · 2015: 17 · 2014: 25 · 2013: 19 · 2012: 25
- FWCI
- 19.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Developmental Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (32551)
- U.S. Public Health Service (37489, 32551)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (TG32 HD07477)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Developmental Biology › Congenital limb and hand anomalies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- Sonic hedgehog, limb development, autopod, apical ectodermal ridge, FGF8, GDF5, zone of polarizing activity, cell death
- MeSH terms
- Animals, Cell Division, Chick Embryo, Ectoderm, Extremities, Fibroblast Growth Factors, Forelimb, Hindlimb, Mesoderm, Transplantation, Heterologous, Trans-Activators, Cell Death, Gene Deletion, Mice, Knockout, Gene Expression Regulation, Developmental, Limb Buds, Body Patterning, In Situ Nick-End Labeling, Mice, Fibroblast Growth Factor 8, Hedgehog Proteins
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