Abstract
During limb development, fibroblast growth factors (Fgfs) govern proximal–distal outgrowth and patterning. FGFs also synchronize developmental patterning between the proximal–distal and anterior–posterior axes by maintaining Sonic hedgehog (Shh) expression in cells of the zone of polarizing activity (ZPA) in the distal posterior mesoderm. Shh, in turn, maintains Fgfs in the apical ectodermal ridge (AER) that caps the distal tip of the limb bud. Crosstalk between Fgf and Shh signaling is critical for patterned limb development, but the mechanisms underlying this feedback loop are not well-characterized. Implantation of Fgf beads in the proximal posterior limb bud can maintain SHH expression in the former ZPA domain (evident 3 h after application), while prolonged exposure (24 h) can induce SHH outside of this domain. Although temporally and spatially disparate, comparative analysis of transcriptome data from these different populations accentuated genes involved in SHH regulation. Comparative analysis identified 25 candidates common to both treatments, with eight linked to SHH expression or function. Furthermore, we demonstrated that LHX2, a LIM Homeodomain transcription factor, is an intermediate in the FGF-mediated regulation of SHH. Our data suggest that LHX2 acts as a competency factor maintaining distal posterior SHH expression subjacent to the AER.
Highlights
Limb development generates a structure that has asymmetry along three coordinate axes: proximal–distal (PD), anterior–posterior (AP), and dorsal–ventral (DV)
SHH expression persists in the former zone of polarizing activity (ZPA) domain following implantation of an FGF-laden bead
SHH is detectable as early as 3 h after application; at 24 h, robust SHH expression is induced around the bead (Figure 1B)
Summary
Limb development generates a structure that has asymmetry along three coordinate axes: proximal–distal (PD), anterior–posterior (AP), and dorsal–ventral (DV). Each axis has its own signaling center that mediates patterning. The apical ectodermal ridge (AER), a thickening of ectoderm located along the distal rim of the limb, is a signaling center from which secreted fibroblast growth factors (Fgfs) regulate PD patterning and outgrowth. Sonic hedgehog (Shh) is secreted from a cluster of cells in the distal posterior limb bud mesoderm called the zone of polarizing activity (ZPA) and regulates AP expansion and patterning. The dorsal ectoderm secretes Wnt7a, which dorsalizes the developing limb. Crosstalk among these axes is required to coordinate proper limb patterning [1]
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