Merlin Controls Limb Development and Thumb Formation by Regulating Primary Cilia-Hedgehog Signaling
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ABSTRACT:
PROVIDER: PRJNA1255523 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR33314318_1.fastq.gz | Fastqsanger.gz | |||
| SRR33314318_2.fastq.gz | Fastqsanger.gz | |||
| SRR33314319_1.fastq.gz | Fastqsanger.gz | |||
| SRR33314319_2.fastq.gz | Fastqsanger.gz | |||
| SRR33314320_1.fastq.gz | Fastqsanger.gz |
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Project description:Hedgehog (HH) signaling, transduced at the primary cilium, plays a crucial role in limb longitudinal growth and digit formation, yet its involvement in thumb development has been underestimated. This study identifies Merlin (Nf2) as a novel regulator of limb development, modulating the ciliary trafficking of the HH receptor, Smoothened. Merlin is predominantly expressed in limb buds and growth plates. Conditional knockout of Merlin in limb mesenchyme in mice results in dwarfism, brachydactyly, and thumb hypoplasia, with transcriptomic profiling and molecular analyses revealing disrupted HH signaling. Mechanistically, Merlin interacts with ARF6 to regulate the ciliary transport of Smoothened via RAB11+ vesicles. Importantly, pharmacological enhancement of HH signaling significantly corrected the limb defects caused by Merlin deletion. These findings highlight the essential role of Merlin in regulating longitudinal limb growth and thumb morphogenesis via primary cilia-HH signaling, suggesting potential therapeutic strategies for related limb dysplasias.
2025-05-20 | GSE295650 | GEO
Project description:To investigate the effect of Merlin rescue on cell proliferation in 3D, we grew subcutaneous xenografts from NF2-deficient CH-157MN meningioma cells harboring doxycycline inducible WT-Merlin. Mice were treated with or without doxycycline and Merlin induction was confirmed 24 hours after induction with Western blot. We performed single-cell RNA sequencing on five Merlin-deficient tumors and seven Merlin rescue tumors
2023-08-07 | GSE224347 | GEO
Project description:Basal cell carcinomas (BCCs) rely on Hedgehog (HH) pathway growth signal amplification by the microtubule-based organelle, the primary cilium. Despite naïve tumors responsiveness to Smoothened inhibitors (Smoi), resistance in advanced tumors remains frequent. While the resistant BCCs usually maintain HH pathway activation, squamous cell carcinomas with Ras/MAPK pathway activation also arise, with the molecular basis of tumor type and pathway selection still obscure. Here we identify the primary cilium as a critical determinant controlling tumor pathway switching. Strikingly, Smoi-resistant BCCs possess an increased mutational load in ciliome genes, resulting in reduced primary cilia and HH pathway activation compared to naive or Gorlin patient BCCs. Gene set enrichment analysis of resistant BCCs with a low HH pathway signature reveals increased Ras/MAPK pathway activation. Tissue analysis confirms an inverse relationship between primary cilia presence and Ras/MAPK activation, and primary cilia removal in BCCs potentiates Ras/MAPK pathway activation. Moreover, activating Ras in HH-responsive cell lines confers resistance to both canonical (vismodegib) and non-canonical (aPKC and MRTF inhibitors) HH pathway inhibitors, while conferring sensitivity to MAPK inhibitors. Our results provide new insights into BCC treatment and identify the primary cilium as an important lineage gatekeeper, preventing HH to Ras/MAPK pathway switching.
2018-10-10 | GSE120954 | GEO
Project description:The primary cilium is a signaling compartment that interprets Hedgehog signals through changes of its protein, lipid and second messenger compositions. Here, we combine proximity labeling of cilia with quantitative mass spectrometry to unbiasedly profile the time-dependent alterations of the ciliary proteome in response to Hedgehog. This approach correctly identifies the three factors known to undergo Hedgehog-regulated ciliary redistribution and reveals two such additional proteins. First, we find that a regulatory subunit of the cAMP-dependent protein kinase (PKA) rapidly exits cilia together with the G protein-coupled receptor GPR161 in response to Hedgehog; and we propose that the GPR161/PKA module senses and amplifies cAMP signals to modulate ciliary PKA activity. Second, we identify the phosphatase Paladin as a cell type-specific regulator of Hedgehog signaling that enters primary cilia upon pathway activation. The broad applicability of quantitative ciliary proteome profiling promises a rapid characterization of ciliopathies and their underlying signaling malfunctions.
2021-04-07 | PXD024361 | Pride
Project description:The primary cilium is a signaling compartment that interprets Hedgehog signals through changes of its protein, lipid and second messenger compositions. Here, we combine proximity labeling of cilia with quantitative mass spectrometry to unbiasedly profile the time-dependent alterations of the ciliary proteome in response to Hedgehog. This approach correctly identifies the three factors known to undergo Hedgehog-regulated ciliary redistribution and reveals two such additional proteins. First, we find that a regulatory subunit of the cAMP-dependent protein kinase (PKA) rapidly exits cilia together with the G protein-coupled receptor GPR161 in response to Hedgehog; and we propose that the GPR161/PKA module senses and amplifies cAMP signals to modulate ciliary PKA activity. Second, we identify the phosphatase Paladin as a cell type-specific regulator of Hedgehog signaling that enters primary cilia upon pathway activation. The broad applicability of quantitative ciliary proteome profiling promises a rapid characterization of ciliopathies and their underlying signaling malfunctions.
2021-04-07 | PXD024366 | Pride
Project description:The primary cilium is a signaling compartment that interprets Hedgehog signals through changes of its protein, lipid and second messenger compositions. Here, we combine proximity labeling of cilia with quantitative mass spectrometry to unbiasedly profile the time-dependent alterations of the ciliary proteome in response to Hedgehog. This approach correctly identifies the three factors known to undergo Hedgehog-regulated ciliary redistribution and reveals two such additional proteins. First, we find that a regulatory subunit of the cAMP-dependent protein kinase (PKA) rapidly exits cilia together with the G protein-coupled receptor GPR161 in response to Hedgehog; and we propose that the GPR161/PKA module senses and amplifies cAMP signals to modulate ciliary PKA activity. Second, we identify the phosphatase Paladin as a cell type-specific regulator of Hedgehog signaling that enters primary cilia upon pathway activation. The broad applicability of quantitative ciliary proteome profiling promises a rapid characterization of ciliopathies and their underlying signaling malfunctions.
2021-04-07 | PXD024367 | Pride
Project description:Loss of primary cilia drives switching from Hedgehog to Ras/MAPK pathway
| PRJNA495133 | ENA
Project description:We have found a broad case of tumour suppressor hypersensitivity for Merlin in cancer: Merlin expression in Merlin deficient cells (but not Merlin wild type cells) strongly suppresses proliferation regardless of tumour type or of additional somatic mutations. To study how Merlin selectively induced growth arrest in Merlin-deficient cells, global gene expression regulation by Merlin was examined by microarray in a set of four cell line pairs derived from different tumour types Four Merlin-deficient and four Merlin wild type cell lines derived from four different tissues/tumour types (meninges, thyroid, kidney, breast) were infected with pLEX lentiviruses (Open Biosystems) expressing either wt Merlin or Merlin L46R (a tumour-derived loss-of-function mutant, used as a control). 24 hours after infection, fresh media containing 2.5ug/ml puromycin was added (drug selection) and cells grown for a further 24 hours, i.e. cells were harvested 48hour after infection. RNA was analyzed using GeneChip Human Gene 2.0 ST arrays (Affymetrix). n=2 for Merlin-deficient cell lines; n=1 for Merlin wt cell lines
2015-04-01 | E-GEOD-53494 | biostudies-arrayexpress
Project description:We have found a broad case of tumour suppressor hypersensitivity for Merlin in cancer: Merlin expression in Merlin deficient cells (but not Merlin wild type cells) strongly suppresses proliferation regardless of tumour type or of additional somatic mutations. To study how Merlin selectively induced growth arrest in Merlin-deficient cells, global gene expression regulation by Merlin was examined by microarray in a set of four cell line pairs derived from different tumour types
2015-04-01 | GSE53494 | GEO
Project description:Primary cilium serves as a cellular M-bM-^@M-^\antennaM-bM-^@M-^] to sense environmental signals. Ciliogenesis requires the removal of CP110 to convert the mother centriole into the basal body. Actin dynamics is also critical for cilia formation. How these distinct processes are properly regulated remains unknown. Here we show that miR-129-3p, a microRNA conserved in the vertebrates, controlled cilia assembly by down-regulating both CP110 and four proteins critical for actin dynamics, Arp2, Toca1, abLIM1, and abLIM3. Consistently, blocking miR-129-3p repressed cilia formation in cultured mammalian cells, whereas its overexpression potently induced ciliogenesis in proliferating cells and extraordinary cilia elongation. Moreover, inhibition of miR-129-3p in zebrafish embryos suppressed cilia assembly in the KupfferM-bM-^@M-^Ys vesicle and pronephric duct, leading to developmental abnormalities including curved body, pericardial oedema, and randomised left-right patterning. Our results thus unravel a novel mechanism that orchestrates both the centriole-to-basal body transition and subsequent cilia assembly via microRNA-mediated posttranscriptional regulations. We want to find the targets of miR-129-3p by overexpressing miR-129-3p oligo or control oligo in hTERT-RPE1 cells. Through microarray analysis we could check the downregulated genes and these genes might be the targets of miR-129-3p. RPE1 cells were transfected with control (Ctrl) or miR-129-3p (M129) oligo for 72h, and harvested for RNA extraction and hybridization on Affymetrix microarrays. Two samples: RPE1-Ctrl, RPE1-M129
2012-05-31 | E-GEOD-34846 | biostudies-arrayexpress