Studies in mouse and zebrafish show that vertebrate forelimb development is initiated by retinoic acid (RA). An RA signal leads to transcription of tbx5 in forelimb precursors which is necessary and sufficient for limb development. However, the timing of the RA signaling event has remained controversial as have source tissue and tissue interactions. We have thus determined the contribution of RA to zebrafish pectoral fin development at different developmental stages. Specifically, an early gastrula stage RA signal triggers the process that leads to determination of tbx5-expressing limb precursors, while a later somitogenesis stage RA signal maintains these precursors. Preceding the lack of tbx5-expressing limb precursors in RA deficient zebrafish embryos, aldh1a2 and cyp26a1 expression domains are distorted along the gastrula margin suggesting that positional values in the ventrolateral mesodermal anlagen are affected. We propose that limb precursor determination requires RA dependent specification of lateral plate territories during gastrulation.
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