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| Novel regulatory interactions revealed by studies of murine limb pattern in Wnt-7a and En-1 mutants |
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| Author(s): Cygan JA, Johnson RL, McMahon AP |
| Source: DEVELOPMENT Volume: 124 Issue: 24 Pages: 5021-5032 Published: DEC 1997 |
| Times Cited: 97 References: 44 |
| Abstract: Classical embryological experiments have demonstrated that dorsal-ventral patterning of the vertebrate limb is dependent upon ectodermal signals, One such factor is Wnt-7a, a member of the Wnt family of secreted proteins, which is expressed in the dorsal ectoderm, Loss of Wnt-7a results in the appearance of ventral characteristics in the dorsal half of the distal limb, Conversely, En-1, a homeodomain transcription factor, is expressed exclusively in the ventral ectoderm, where it represses Wnt-7a. Eu-1 mutants have dorsal characteristics in the ventral half of the distal limb, Experiments in the chick suggest that the dorsalizing activity of Wnt-7a in the mesenchyme is mediated through the regulation of the LIM-homeodomain transcription factor Lmx-1, Here we have examined the relationship between Wnt-7a, En-1 and Lmx-1b, a mouse homolog of chick Lmx-1, in patterning the mammalian limb, We find that Wnt-7a is required for Lmx-1b expression in distal limb mesenchyme, and that Lmx-1b activation in the ventral mesenchyme of En-1 mutants requires Wnt-7a. Consistent with Lmx-1b playing a primary role in dorsalization of the limb, we find a direct correlation between regions of the anterior distal limb in which Lmx-1b is misregulated during limb development and the localization of dorsal-ventral patterning defects in Tnt-7a and En-1 mutant adults, Thus, ectopic Wnt-7a expression and Lmx-1b activation underlie the dorsalized En-1 phenotype, although our analysis also reveals a Wnt-7a-independent activity for En-1 in the repression of pigmentation in the ventral epidermis, Finally, we demonstrate that ectopic expression of Wnt-7a in the ventral limb ectoderm of En-1 mutants results in the formation of a second, ventral apical ectodermal ridge (AER) at the junction between Wnt-7a-expressing and nonexpressing ectoderm, Unlike the normal AER, ectopic AER formation is dependent upon Wnt-7a activity, indicating that distinct genetic mechanisms may be involved in primary and secondary AER formation. |
| Document Type: Article |
| Language: English |
| Reprint Address: McMahon, AP (reprint author), Harvard Univ, Biolabs, Dept Mol & Cellular Biol, 16 Divin Ave, Cambridge, MA 02138 USA |
Addresses:
1. Harvard Univ, Biolabs, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA
2. Univ Texas, MD Anderson Cancer Ctr, Dept Biochem & Mol Biol, Houston, TX 77030 USA |
| Publisher: COMPANY OF BIOLOGISTS LTD, BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE, CAMBS, ENGLAND CB4 4DL |
| Subject Category: Developmental Biology |
| IDS Number: YP435 |
| ISSN: 0950-1991 |
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