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Characterization of FGF-Mediated Sonic Hedgehog Expression During Limb Development
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Characterization of FGF-Mediated Sonic Hedgehog Expression During Limb Development
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Characterization of FGF-Mediated Sonic Hedgehog Expression During Limb Development
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Dissertation
Characterization of FGF-Mediated Sonic Hedgehog Expression During Limb Development
2018
Overview
Crosstalk between Fibroblast Growth Factors (FGFs) and Sonic hedgehog (SHH) is essential for proper limb development; however, the molecular mechanisms involved in this process remain unclear. Via comparative transcriptome analysis and gene knockdown and overexpression studies, we identified the transcription factor Lim homeobox 2 (LHX2) as an intermediate in FGF-directed SHH expression. We determined that FGF signaling was necessary for LHX2 expression and demonstrated that LHX2 is a primary transcription target of FGF signaling through the RAS and AKT pathways. Additionally, loss of LHX2 in the distal limb results in decreased SHH expression and a truncated limb within 24 hours of treatment, while overexpression of LHX2 in the presence of ectopic FGF leads to increased SHH expression. While LHX2 is insufficient alone to induce SHH, we conclude that it likely serves as a competency factor for endogenous SHH expression, keeping it juxtaposed to the distal apical ectodermal ridge during limb outgrowth.
