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Timed deletion of Twist1 in the limb bud reveals age-specific impacts on autopod and zeugopod patterning.

ABSTRACT: Twist1 encodes a transcription factor that plays a vital role in limb development. We have used a tamoxifen-inducible Cre transgene, Ubc-CreERT2, to generate time-specific deletions of Twist1 by inducing Cre activity in mouse embryos at different ages from embryonic (E) day 9.5 onwards. A novel forelimb phenotype of supernumerary pre-axial digits and enlargement or partial duplication of the distal radius was observed when Cre activity was induced at E9.5. Gene expression analysis revealed significant upregulation of Hoxd10, Hoxd11 and Grem1 in the anterior half of the forelimb bud at E11.5. There is also localized upregulation of Ptch1, Hand2 and Hoxd13 at the site of ectopic digit formation, indicating a posterior molecular identity for the supernumerary digits. The specific skeletal phenotypes, which include duplication of digits and distal zeugopods but no overt posteriorization, differ from those of other Twist1 conditional knockout mutants. This outcome may be attributed to the deferment of Twist1 ablation to a later time frame of limb morphogenesis, which leads to the ectopic activation of posterior genes in the anterior tissues after the establishment of anterior-posterior anatomical identities in the forelimb bud.

SUBMITTER: Loebel DA

PROVIDER: S-EPMC4044014 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Timed deletion of Twist1 in the limb bud reveals age-specific impacts on autopod and zeugopod patterning.

Loebel David A F DA Hor Angelyn C C AC Bildsoe Heidi K HK Tam Patrick P L PP

PloS one 20140603 6

Twist1 encodes a transcription factor that plays a vital role in limb development. We have used a tamoxifen-inducible Cre transgene, Ubc-CreERT2, to generate time-specific deletions of Twist1 by inducing Cre activity in mouse embryos at different ages from embryonic (E) day 9.5 onwards. A novel forelimb phenotype of supernumerary pre-axial digits and enlargement or partial duplication of the distal radius was observed when Cre activity was induced at E9.5. Gene expression analysis revealed signi ...[more]

PMID: 24893291

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Project description:BackgroundThe bat has strikingly divergent forelimbs (long digits supporting wing membranes) and hindlimbs (short, typically free digits) due to the distinct requirements of both aerial and terrestrial locomotion. During embryonic development, the morphology of the bat forelimb deviates dramatically from the mouse and chick, offering an alternative paradigm for identifying genes that play an important role in limb patterning.ResultsUsing transcriptome analysis of developing Natal long-fingered bat (Miniopterus natalensis) fore- and hindlimbs, we demonstrate that the transcription factor Meis2 has a significantly higher expression in bat forelimb autopods compared to hindlimbs. Validation by reverse transcriptase and quantitative polymerase chain reaction (RT-qPCR) and whole mount in situ hybridisation shows that Meis2, conventionally known as a marker of the early proximal limb bud, is upregulated in the bat forelimb autopod from CS16. Meis2 expression is localised to the expanding interdigital webbing and the membranes linking the wing to the hindlimb and tail. In mice, Meis2 is also expressed in the interdigital region prior to tissue regression. This interdigital Meis2 expression is not activated by retinoic acid (RA) signalling as it is present in the retained interdigital tissue of Rdh10 (trex/trex) mice, which lack RA. Additionally, genes encoding RA-synthesising enzymes, Rdh10 and Aldh1a2, and the RA nuclear receptor Rarβ are robustly expressed in bat fore- and hindlimb interdigital tissues indicating that the mechanism that retains interdigital tissue in bats also occurs independently of RA signalling.ConclusionsMammalian interdigital Meis2 expression, and upregulation in the interdigital webbing of bat wings, suggests an important role for Meis2 in autopod development. Interdigital Meis2 expression is RA-independent, and retention of interdigital webbing in bat wings is not due to the suppression of RA-induced cell death. Rather, RA signalling may play a role in the thinning (rather than complete loss) of the interdigital tissue in the bat forelimb, while Meis2 may interact with other factors during both bat and mouse autopod development to maintain a pool of interdigital cells that contribute to digit patterning and growth.

Dataset Information

Timed deletion of Twist1 in the limb bud reveals age-specific impacts on autopod and zeugopod patterning.

Publications

Timed deletion of Twist1 in the limb bud reveals age-specific impacts on autopod and zeugopod patterning.

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