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

Watson, Billy A.; Feenstra, Jennifer M.; Arsdale, Jonathan M Van; Rai-Bhatti, Karndeep S; Kim, Diana J H; Coggins, Ashley; Mattison, Gennaya; Yoo, Stephen; Steinman, Eric D; Pira, Charmaine U.; Gongol, Brendan; Oberg, Kerby C.

doi:10.3390/jdb6020013

Cited by 13 publications

(9 citation statements)

References 83 publications

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“…This mechanism remains unclear in this study and will certainly require further experimentation in the future. However, supportive to our findings, the FGF2–SHH axis is described for limb development in mice where FGF2 maintains SHH expression and SHH, in turn, maintains FGF2 [ 28 ]. Combined treatment of hESC-derived endodermal cells (d4) with FGF2 and small molecule inhibitors of the FGF receptor pathways brought evidence that SHH expression is induced via MEK/ERK signaling.…”

Section: Discussionsupporting

confidence: 89%

FGF2 Inhibits Early Pancreatic Lineage Specification during Differentiation of Human Embryonic Stem Cells

Dettmer

Cirksena

Münchhoff

et al. 2020

Cells

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Growth factors are important regulators during organ development. For many vertebrates (but not humans) it is known how they contribute to the formation and expansion of PDX1-positive cells during pancreas organogenesis. Here, the effects of the fibroblast growth factors FGF2, FGF7, FGF10, and epidermal growth factor (EGF) on pancreas development in humans were assessed by using human pluripotent stem cells (hPSCs). During this, FGF2 was identified as a potent anti-pancreatic factor whereas FGF7, FGF10, and EGF increased the cell mass while retaining PDX1-positivity. FGF2 increased the expression of the anti-pancreatic factor sonic hedgehog (SHH) while suppressing PDX1 in a dose-dependent manner. Differentiating cells secreted SHH to the medium and we interrogated the cells’ secretome during differentiation to globally examine the composition of secreted signaling factors. Members of the TGF-beta-, Wnt-, and FGF-pathways were detected. FGF17 showed a suppressive anti-pancreatic effect comparable to FGF2. By inhibition of specific branches of FGF-receptor signaling, we allocated the SHH-induction by FGF2 to MEK/ERK-signaling and the anti-pancreatic effect of FGF2 to the receptor variant FGFR1c or 3c. Altogether, we report findings on the paracrine activity of differentiating hPSCs during generation of pancreatic progenitors. These observations suggest a different role for FGF2 in humans compared to animal models of pancreas organogenesis.

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Section: Discussionsupporting

confidence: 89%

FGF2 Inhibits Early Pancreatic Lineage Specification during Differentiation of Human Embryonic Stem Cells

Dettmer

Cirksena

Münchhoff

et al. 2020

Cells

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“…Our results were consistent with previous reports that FGF signaling was required for LHX9 expression in the development of brain, eyes and limb [1, 10, 48]. In addition, other LHX members, such as LHX2, mediated the FGF-Sonic hedgehog (SHH) regulatory loop in limb development [45]; LHX8 expression was regulated by retinoic acid through FGF-8b in the upper jaw development of chicken embryo [40]; LHX6 and LHX7 was regulated by different FGF ligands during the branchial arch and tooth development in zebrafish [20]. In all, our data further confirmed that FGF-TGF-β signaling crosstalk was the key regulator of LHX9 expression and function in the proliferation, migration and metastasis of OS cells.…”

Section: Discussionsupporting

confidence: 93%

FGF-induced LHX9 regulates the progression and metastasis of osteosarcoma via FRS2/TGF-β/β-catenin pathway

Li¹,

Tu²,

Lü³

et al. 2019

Cell Div

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Background: Fibroblast growth factor (FGF) and tumor growth factor-β (TGFβ) have emerged as pivotal regulators during the progression of osteosarcoma (OS). LHX9 is one crucial transcription factor controlled by FGF, however, its function in OS has not been investigated yet. Methods: The expression of LHX9, FRS2, BMP4, TGF-beta R1, SMAD2, beta-catenin and metastasis-related proteins was measured by real-time quantitative PCR (RT-qPCR) and Western blot. CCK-8 assay and colony formation assay were employed to determine the proliferation of OS cells, while scratch wound healing assay and transwell assay were used to evaluate their migration and invasion, respectively. In vivo tumor growth and metastasis were determined by subcutaneous or intravenous injection of OS cells into nude mice. Results: LHX9 expression was evidently up-regulated in OS tumor tissues and cell lines. Knockdown of LHX9 impaired the proliferation, migration, invasion and metastasis of OS cells. Mechanistically, LHX9 silencing led to the downregulation of BMP-4, β-catenin and metastasis-related proteins, which was also observed in beta-catenin knockdown OS cells. By contrast, FRS2 knockdown conduced to the up-regulation of LHX9, BMP4, β-catenin and TGF-βR1, while TGF-beta inhibition repressed the expression of LHX9 and metastasis-related proteins. Additionally, let-7c modulates LHX9 and metastasis-related proteins by suppressing TGF-beta R1 expression on transcriptional level. Conclusions: This study revealed LHX9 was essential for the proliferation, migration, invasion, and metastasis of OS cells via FGF and TGF-β/β-catenin signaling pathways.

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“…lhx2b was expressed in the entire fin bud mesenchymal cells at 1 and 2 dpf (Additional file 3C–F). Similarly, an ortholog of the lhx2b gene, lhx2 , is expressed in the entire fin/limb bud mesenchyme in a basal actinopterygian, a polyodon, and tetrapods [19, 34–36]. In gt223A, the gene trap construct had integrated within the lhx9 gene (Additional file 2B), and the UAS:GFP reporter was expressed in the anterior part of the fin bud at day 2 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…5), indicating that the lhx2b gene is expressed in fin ray premature mesenchymal cells. The expression pattern of lhx2 , the tetrapod ortholog of lhx2b , is regulated by Shh signaling from the ZPA, and lhx2 reciprocally regulates shh expression for AP patterning and maintains the undifferentiated state of mesenchymal cells in the limb bud [35, 36]. In zebrafish and paddlefish, the shh gene is expressed in posterior mesenchymal cells of the developing fin fold region as well as in the early larval pectoral fin mesenchyme [19, 48].…”

Section: Discussionmentioning

confidence: 99%

Pattern of fin rays along the antero-posterior axis based on their connection to distal radials

Hamada¹,

Uemoto²,

Tanaka³

et al. 2019

Zoological Lett

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Background Teleost paired fins are composed of two endoskeletal domains, proximal and distal radials, and an exoskeletal domain, the fin ray. The zebrafish pectoral fin displays elaborately patterned radials along the anteroposterior (AP) axis. Radials are considered homologous to tetrapod limb skeletons, and their patterning mechanisms in embryonic development are similar to those of limb development. Nevertheless, the pattern along the AP axis in fin rays has not been well described in the zebrafish pectoral fin, although several recent reports have revealed that fin ray development shares some cellular and genetic properties with fin/limb endoskeleton development. Thus, fin ray morphogenesis may involve developmental mechanisms for AP patterning in the fin/limb endoskeleton, and may have a specific pattern along the AP axis. Results We conducted detailed morphological observations on fin rays and their connection to distal radials by comparing intra- and inter-strain zebrafish specimens. Although the number of fin rays varied, pectoral fin rays could be categorized into three domains along the AP axis, according to the connection between the fin rays and distal radials; additionally, the number of fin rays varied in the posterior part of the three domains. This result was confirmed by observation of the morphogenesis process of fin rays and distal radials, which showed altered localization of distal radials in the middle domain. We also evaluated the expression pattern of lhx genes, which have AP patterning activity in limb development, in fin rays and during distal radial development and found these genes to be expressed during morphogenesis in both fin rays and distal radials. Conclusion The fin ray and its connection to the endoskeleton are patterned along the AP axis, and the pattern along the AP axis in the fin ray and the radial connection is constructed by the developmental mechanism related to AP patterning in the limb/fin bud. Our results indicate the possibility that the developmental mechanisms of fin rays and their connection are comparable to those of the distal element of the limb skeleton.

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

Cited by 13 publications

References 83 publications

FGF2 Inhibits Early Pancreatic Lineage Specification during Differentiation of Human Embryonic Stem Cells

FGF2 Inhibits Early Pancreatic Lineage Specification during Differentiation of Human Embryonic Stem Cells

FGF-induced LHX9 regulates the progression and metastasis of osteosarcoma via FRS2/TGF-β/β-catenin pathway

Pattern of fin rays along the antero-posterior axis based on their connection to distal radials

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