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J. Dev. Biol. 2018, 6(2), 13; https://doi.org/10.3390/jdb6020013

LHX2 Mediates the FGF-to-SHH Regulatory Loop during Limb Development

1
Department of Pathology and Human Anatomy, School of Medicine, Loma Linda University, Loma Linda, CA 92354, USA
2
Division of Microbiology and Molecular Genetics, Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA 92354, USA
3
Department of Cardiopulmonary Sciences, School of Allied Health Professions, Loma Linda University, Loma Linda, CA 92354, USA
*
Author to whom correspondence should be addressed.
Received: 30 May 2018 / Revised: 11 June 2018 / Accepted: 12 June 2018 / Published: 15 June 2018
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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. View Full-Text
Keywords: limb development; fibroblast growth factor (FGF); sonic hedgehog (SHH); LIM Homeobox 2 (LHX2) limb development; fibroblast growth factor (FGF); sonic hedgehog (SHH); LIM Homeobox 2 (LHX2)
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Watson, B.A.; Feenstra, J.M.; Van Arsdale, J.M.; Rai-Bhatti, K.S.; Kim, D.J.H.; Coggins, A.S.; Mattison, G.L.; Yoo, S.; Steinman, E.D.; Pira, C.U.; Gongol, B.R.; Oberg, K.C. LHX2 Mediates the FGF-to-SHH Regulatory Loop during Limb Development. J. Dev. Biol. 2018, 6, 13.

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