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Overgrowth of a mouse model of Simpson-Golabi-Behmel syndrome is partly mediated by Indian hedgehog.

ABSTRACT: Loss-of-function mutations of Glypican 3 (Gpc3) cause the Simpson-Golabi-Behmel overgrowth syndrome (SGBS), and developmental overgrowth is observed in Gpc3-null mice, a mouse model for SGBS. We recently reported that GPC3 inhibits Hedgehog (Hh) signalling by inducing its endocytosis and degradation. Here, we show that the developmental overgrowth observed in Gpc3-null mice is, at least in part, a consequence of the hyperactivation of the Hh pathway. We bred Gpc3-null mice with mice that are Hh signalling-deficient owing to the lack of Indian Hh (Ihh), one of the three mammalian Hhs. We found that the Gpc3-null mice showed a 29.9% overgrowth in an Ihh wild-type background, whereas an Ihh-null background partly rescues the overgrowth caused by the lack of Gpc3 as the double mutants were 19.8% bigger than the Ihh-null mice. Consistent with the role of GPC3 in Hh endocytosis and degradation, the Gpc3-null mice show increased levels of Ihh protein and signalling, but similar levels of Ihh messenger RNA.

SUBMITTER: Capurro MI

PROVIDER: S-EPMC2726674 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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Overgrowth of a mouse model of Simpson-Golabi-Behmel syndrome is partly mediated by Indian hedgehog.

Capurro Mariana I MI Li Fuchuan F Filmus Jorge J

EMBO reports 20090710 8

Loss-of-function mutations of Glypican 3 (Gpc3) cause the Simpson-Golabi-Behmel overgrowth syndrome (SGBS), and developmental overgrowth is observed in Gpc3-null mice, a mouse model for SGBS. We recently reported that GPC3 inhibits Hedgehog (Hh) signalling by inducing its endocytosis and degradation. Here, we show that the developmental overgrowth observed in Gpc3-null mice is, at least in part, a consequence of the hyperactivation of the Hh pathway. We bred Gpc3-null mice with mice that are Hh ...[more]

PMID: 19590577

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Project description:IntroductionObesity is a major health problem because it is associated with increased risk of cardiovascular disease, diabetes, hypertension, and some cancers. Strategies to prevent or reduce obesity focus mainly on the possible effects of natural compounds that can induce a phenotype of browning adipocytes capable of releasing energy in the form of heat. Allicin, a bioactive component of garlic with numerous pharmacological functions, is known to stimulate energy metabolism.MethodsIn the present study, the effects of allicin on human Simpson-Golabi-Behmel Syndrome (SGBS) cells were investigated by quantifying the dynamics of lipid droplets (LDs) and mitochondria, as well as transcriptomic changes after six days of differentiation.ResultsAllicin significantly promoted the reduction in the surface area and size of LDs, leading to the formation of multilocular adipocytes, which was confirmed by the upregulation of genes related to lipolysis. The increase in the number and decrease in the mean aspect ratio of mitochondria in allicin-treated cells indicate a shift in mitochondrial dynamics toward fission. The structural results are confirmed by transcriptomic analysis showing a significant arrangement of gene expression associated with beige adipocytes, in particular increased expression of T-box transcription factor 1 (TBX1), uncoupling protein 1 (UCP1), PPARG coactivator 1 alpha (PPARGC1A), peroxisome proliferator-activated receptor alpha (PPARA), and OXPHOS-related genes. The most promising targets are nuclear genes such as retinoid X receptor alpha (RXRA), retinoid X receptor gamma (RXRG), nuclear receptor subfamily 1 group H member 3 (NR1H3), nuclear receptor subfamily 1 group H member 4 (NR1H4), PPARA, and oestrogen receptor 1 (ESR1).DiscussionTranscriptomic data and the network pharmacology-based approach revealed that genes and potential targets of allicin are involved in ligand-activated transcription factor activity, intracellular receptor signalling, regulation of cold-induced thermogenesis, and positive regulation of lipid metabolism. The present study highlights the potential role of allicin in triggering browning in human SGBS cells by affecting the LD dynamics, mitochondrial morphology, and expression of brown marker genes. Understanding the potential targets through which allicin promotes this effect may reveal the underlying signalling pathways and support these findings.

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Overgrowth of a mouse model of Simpson-Golabi-Behmel syndrome is partly mediated by Indian hedgehog.

Publications

Overgrowth of a mouse model of Simpson-Golabi-Behmel syndrome is partly mediated by Indian hedgehog.

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