ArticleDevelopmental biology2013
Sonic hedgehog signaling directly targets Hyaluronic Acid Synthase 2, an essential regulator of phalangeal joint patterning.
Article in Developmental biology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 26 citations in OpenAlex.
- Suppression of apoptosis impairs phalangeal joint formation in the pathogenesis of brachydactyly type A1.Nature communications · 2024Article
- STIGMA: Single-cell tissue-specific gene prioritization using machine learning.American journal of human genetics · 2024Article
- Integrated PK/PD Modeling Relates Smoothened Inhibitor Biomarkers to The Heterogeneous Intratumor Disposition of Cetuximab in Pancreatic Cancer Tumor Models.Journal of pharmaceutical sciences · 2024Article
- Synovial joint cavitation initiates with microcavities in interzone and is coupled to skeletal flexion and elongation in developing mouse embryo limbs.Biology open · 2022Article
- Hyaluronan synthase 2, a target of miR-200c, promotes carbon tetrachloride-induced acute and chronic liver inflammation via regulation of CCL3 and CCL4.Experimental & molecular medicine · 2022Article
- Article
- HAS3-induced extracellular vesicles from melanoma cells stimulate IHH mediated c-Myc upregulation via the hedgehog signaling pathway in target cells.Cellular and molecular life sciences : CMLS · 2020Article
- Hyaluronic acid is required for palatal shelf movement and its interaction with the tongue during palatal shelf elevation.Developmental biology · 2020Article
- Tumor Priming by SMO Inhibition Enhances Antibody Delivery and Efficacy in a Pancreatic Ductal Adenocarcinoma Model.Molecular cancer therapeutics · 2019Article
- Hyaluronan synthase 2-mediated hyaluronan production mediates Notch1 activation and liver fibrosis.Science translational medicine · 2019Article
- Primary cilia defects causing mitral valve prolapse.Science translational medicine · 2019Article
- Human pre-valvular endocardial cells derived from pluripotent stem cells recapitulate cardiac pathophysiological valvulogenesis.Nature communications · 2019Article
- Secreted metalloproteases ADAMTS9 and ADAMTS20 have a non-canonical role in ciliary vesicle growth during ciliogenesis.Nature communications · 2019Article
- Transcription factor TBX4 regulates myofibroblast accumulation and lung fibrosis.The Journal of clinical investigation · 2016Article
- Hyaluronan as a therapeutic target in human diseases.Advanced drug delivery reviews · 2016Review
- The importance of foetal movement for co-ordinated cartilage and bone development in utero : clinical consequences and potential for therapy.Bone & joint research · 2015Review
- Hyaluronan: a simple polysaccharide with diverse biological functions.Acta biomaterialia · 2014Review
- The Purkinje neuron acts as a central regulator of spatially and functionally distinct cerebellar precursors.Developmental cell · 2013Article
Corrections and comments
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Authors and funding
6 authors at 4 institutions in 1 country.
Funding
Abstract
Sonic hedgehog (Shh) signal, mediated by the Gli family of transcription factors, plays an essential role in the growth and patterning of the limb. Through analysis of the early limb bud transcriptome, we identified a posteriorly-enriched gene, Hyaluronic Acid Synthase 2 (Has2), which encodes a key enzyme for the synthesis of hyaluronan (HA), as a direct target of Gli transcriptional regulation during early mouse limb development. Has2 expression in the limb bud is lost in Shh null and expanded anteriorly in Gli3 mutants. We identified an ∼3kb Has2 promoter fragment that contains two strong Gli-binding consensus sequences, and mutation of either site abrogated the ability of Gli1 to activate Has2 promoter in a cell-based assay. Additionally, this promoter fragment is sufficient to direct expression of a reporter gene in the posterior limb mesenchyme. Chromatin immunoprecipitation of DNA-Gli3 protein complexes from limb buds indicated that Gli3 strongly binds to the Has2 promoter region, suggesting that Has2 is a direct transcriptional target of the Shh signaling pathway. We also showed that Has2 conditional mutant (Has2cko) hindlimbs display digit-specific patterning defects with longitudinally shifted phalangeal joints and impaired chondrogenesis. Has2cko limbs show less capacity for mesenchymal condensation with mislocalized distributions of chondroitin sulfate proteoglycans (CSPGs), aggrecan and link protein. Has2cko limb phenotype displays striking resemblance to mutants with defective chondroitin sulfation suggesting tight developmental control of HA on CSPG function. Together, our study identifies Has2 as a novel downstream target of Shh signaling required for joint patterning and chondrogenesis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.