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Reversal of hyperactive Wnt signaling-dependent adipocyte defects by peptide boronic acids.

ABSTRACT: Deregulated Wnt signaling and altered lipid metabolism have been linked to obesity, diabetes, and various cancers, highlighting the importance of identifying inhibitors that can modulate Wnt signaling and aberrant lipid metabolism. We have established a Drosophila model with hyperactivated Wnt signaling caused by partial loss of axin, a key component of the Wnt cascade. The Axin mutant larvae are transparent and have severe adipocyte defects caused by up-regulation of ?-catenin transcriptional activities. We demonstrate pharmacologic mitigation of these phenotypes in Axin mutants by identifying bortezomib and additional peptide boronic acids. We show that the suppressive effect of peptide boronic acids on hyperactive Wnt signaling is dependent on ?-catenin; the rescue effect is completely abolished with the depletion of ?-catenin in adipocytes. These results indicate that rather than targeting the canonical Wnt signaling pathway directly, pharmacologic modulation of ?-catenin activity through ?-catenin is a potentially attractive approach to attenuating Wnt signaling in vivo.

SUBMITTER: Zhang T

PROVIDER: S-EPMC5594642 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Reversal of hyperactive Wnt signaling-dependent adipocyte defects by peptide boronic acids.

Zhang Tianyi T Hsu Fu-Ning FN Xie Xiao-Jun XJ Li Xiao X Liu Mengmeng M Gao Xinsheng X Pei Xun X Liao Yang Y Du Wei W Ji Jun-Yuan JY

Proceedings of the National Academy of Sciences of the United States of America 20170821 36

Deregulated Wnt signaling and altered lipid metabolism have been linked to obesity, diabetes, and various cancers, highlighting the importance of identifying inhibitors that can modulate Wnt signaling and aberrant lipid metabolism. We have established a <i>Drosophila</i> model with hyperactivated Wnt signaling caused by partial loss of axin, a key component of the Wnt cascade. The <i>Axin</i> mutant larvae are transparent and have severe adipocyte defects caused by up-regulation of β-catenin tra ...[more]

PMID: 28827348

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Project description:Defects in blood development frequently occur among syndromic congenital anomalies. Thrombocytopenia-Absent Radius (TAR) syndrome is a rare congenital condition with reduced platelets (hypomegakaryocytic thrombocytopenia) and forelimb anomalies, concurrent with more variable heart and kidney defects. TAR syndrome associates with hypomorphic gene function for RBM8A/Y14 that encodes a component of the exon junction complex involved in mRNA splicing, transport, and nonsense-mediated decay. How perturbing a general mRNA-processing factor causes the selective TAR Syndrome phenotypes remains unknown. Here, we connect zebrafish rbm8a perturbation to early hematopoietic defects via attenuated non-canonical Wnt/Planar Cell Polarity (PCP) signaling that controls developmental cell re-arrangements. In hypomorphic rbm8a zebrafish, we observe a significant reduction of cd41-positive thrombocytes. rbm8a-mutant zebrafish embryos accumulate mRNAs with individual retained introns, a hallmark of defective nonsense-mediated decay; affected mRNAs include transcripts for non-canonical Wnt/PCP pathway components. We establish that rbm8a-mutant embryos show convergent extension defects and that reduced rbm8a function interacts with perturbations in non-canonical Wnt/PCP pathway genes wnt5b, wnt11f2, fzd7a, and vangl2. Using live-imaging, we found reduced rbm8a function impairs the architecture of the lateral plate mesoderm (LPM) that forms hematopoietic, cardiovascular, kidney, and forelimb skeleton progenitors as affected in TAR Syndrome. Both mutants for rbm8a and for the PCP gene vangl2 feature impaired expression of early hematopoietic/endothelial genes including runx1 and the megakaryocyte regulator gfi1aa. Together, our data propose aberrant LPM patterning and hematopoietic defects as consequence of attenuated non-canonical Wnt/PCP signaling upon reduced rbm8a function. These results also link TAR Syndrome to a potential LPM origin and a developmental mechanism.

Dataset Information

Reversal of hyperactive Wnt signaling-dependent adipocyte defects by peptide boronic acids.

Publications

Reversal of hyperactive Wnt signaling-dependent adipocyte defects by peptide boronic acids.

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