Dataset Information

ISLET1-Dependent ?-Catenin/Hedgehog Signaling Is Required for Outgrowth of the Lower Jaw.

ABSTRACT: Mandibular patterning information initially resides in the epithelium during development. However, how transcriptional regulation of epithelium-derived signaling controls morphogenesis of the mandible remains elusive. Using ShhCre to target the mandibular epithelium, we ablated transcription factor Islet1, resulting in a distally truncated mandible via unbalanced cell apoptosis and decreased cell proliferation in the distal mesenchyme. Loss of Islet1 caused a lack of cartilage at the distal tip, leading the fusion of two growing mandibular elements surrounding the rostral process of Meckel's cartilage. Loss of Islet1 results in dysregulation of mesenchymal genes important for morphogenesis of the mandibular arch. We revealed that Islet1 is required for the activation of epithelial ?-catenin signaling via repression of Wnt antagonists. Reactivation of ?-catenin in the epithelium of the Islet1 mutant rescued mandibular morphogenesis through sonic hedgehog (SHH) signaling to the mesenchyme. Furthermore, overexpression of a transgenic hedgehog ligand in the epithelium also partially restored outgrowth of the mandible. These data reveal functional roles for an ISLET1-dependent network integrating ?-catenin/SHH signals in mesenchymal cell survival and outgrowth of the mandible during development.

SUBMITTER: Li F

PROVIDER: S-EPMC5376631 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Publications

ISLET1-Dependent β-Catenin/Hedgehog Signaling Is Required for Outgrowth of the Lower Jaw.

Li Feixue F Fu Guoquan G Liu Ying Y Miao Xiaoping X Li Yan Y Yang Xueqin X Zhang Xiaoyun X Yu Dongliang D Gan Lin L Qiu Mengsheng M Chen Yiping Y Zhang Ze Z Zhang Zunyi Z

Molecular and cellular biology 20170331 8

Mandibular patterning information initially resides in the epithelium during development. However, how transcriptional regulation of epithelium-derived signaling controls morphogenesis of the mandible remains elusive. Using ShhCre to target the mandibular epithelium, we ablated transcription factor Islet1, resulting in a distally truncated mandible via unbalanced cell apoptosis and decreased cell proliferation in the distal mesenchyme. Loss of Islet1 caused ...[more]

PMID: 28069742

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Project description:Sonic Hedgehog (Shh) signaling induces neovascularization and angiogenesis. It is not known whether the hedgehog signaling pathway in endothelial cells is essential to angiogenesis. Smoothened (Smo) transduces hedgehog signaling across the cell membrane. This study assessed whether endothelial Smoothened-dependent Shh signaling is required for Shh-mediated angiogenesis and ischemic tissue repair. Endothelial-specific smoothened knockout mice, eSmoNull were created using Cre-lox recombination system. eSmoNull mice had no observable phenotype at baseline and showed normal cardiac function. Smoothened in CD31+ cells isolated from eSmoNull hearts was significantly reduced compared to CD31+ cells from eSmoWT littermate control hearts. Fluorescence immunostaining of eSmoNull heart sections showed Smo expression in endothelial cells was abolished. The hind-limb ischemia (HLI) model was used to assess the response to ischemic injury. Perfusion ratio, limb motor function, and limb necrosis were not significantly different after HLI between eSmoNull mice and eSmoWT. Capillary densities in the ischemic limb in eSmoNull mice were also similar to eSmoWT at 4 weeks after HLI. Next, response to exogenous Shh was assessed in the corneal angiogenesis model. There was no significant difference in corneal angiogenesis induced by administration of Shh pellets between eSmoWT and eSmoNull mice. Furthermore, in vitro experiments demonstrated that direct Shh had limited effects on endothelial cell proliferation and migration. However, conditioned media from Shh-treated fibroblasts had a more potent effect on endothelial cell proliferation and migration than non-treated conditioned media. Furthermore, Shh treatment of fibroblasts dramatically stimulated angiogenic growth factor expression, including PDGF-B, VEGF-A, HGF and IGF. PDGF-B was the most upregulated and may contribute to the large neo-vessels associated with Shh-induced angiogenesis. Taken together, these data demonstrate that Shh signaling via Smoothened in endothelial cells is not required for angiogenesis and ischemic tissue repair. Shh signaling via stromal cells likely mediates its angiogenic effects.

Dataset Information

ISLET1-Dependent ?-Catenin/Hedgehog Signaling Is Required for Outgrowth of the Lower Jaw.

Publications

ISLET1-Dependent β-Catenin/Hedgehog Signaling Is Required for Outgrowth of the Lower Jaw.

Similar Datasets

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