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Hedgehog-Activated Fat4 and PCP Pathways Mediate Mesenchymal Cell Clustering and Villus Formation in Gut Development.

Abilasha Rao-Bhatia | Min Zhu | Wen-Chi Yin | Sabrina Coquenlorge | Xiaoyun Zhang | Janghee Woo | Yu Sun | Charlotte H Dean | Aimin Liu | Chi-Chung Hui | Ramesh A Shivdasani | Helen McNeill | Sevan Hopyan | Tae-Hee Kim
Developmental cell | 2020

During development, intestinal epithelia undergo dramatic morphogenesis mediated by mesenchymal signaling to form villi, which are required for efficient nutrient absorption and host defense. Although both smooth-muscle-induced physical forces and mesenchymal cell clustering beneath emerging villi are implicated in epithelial folding, the underlying cellular mechanisms are unclear. Hedgehog (Hh) signaling can mediate both processes. We therefore analyzed its direct targetome and revealed GLI2 transcriptional activation of atypical cadherin and planar cell polarity (PCP) genes. By examining Fat4 and Dchs1 knockout mice, we demonstrate their critical roles in villus formation. Analyses of PCP-mutant mice and genetic interaction studies show that the Fat4-Dchs1 axis acts in parallel to the core-Vangl2 PCP axis to control mesenchymal cell clustering. Moreover, live light-sheet fluorescence microscopy and cultured PDGFRα+ cells reveal a requirement for PCP in their oriented cell migration guided by WNT5A. Therefore, mesenchymal PCP induced by Hh signaling drives cell clustering and subsequent epithelial remodeling.

Pubmed ID: 32155439

Associated grants

  • Agency: NIDDK NIH HHS, United States
    Id: R01 DK081113
  • Agency: CIHR, Canada

Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.

This is a list of tools and resources that we have found mentioned in this publication.


PANTHER (tool)

RRID:SCR_004869

System that classifies genes by their functions, using published scientific experimental evidence and evolutionary relationships to predict function even in absence of direct experimental evidence. Orthologs view is curated orthology relationships between genes for human, mouse, rat, fish, worm, and fly.

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REViGO (tool)

RRID:SCR_005825

Web server that summarizes lists of Gene Ontology terms by removing redundant terms and visualizing the remaining ones in scatterplots, interactive graphs, treemaps, or tag clouds. Platform: Online tool

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BEDTools (tool)

RRID:SCR_006646

A powerful toolset for genome arithmetic allowing one to address common genomics tasks such as finding feature overlaps and computing coverage. Bedtools allows one to intersect, merge, count, complement, and shuffle genomic intervals from multiple files in widely-used genomic file formats such as BAM, BED, GFF/GTF, VCF. While each individual tool is designed to do a relatively simple task (e.g., intersect two interval files), quite sophisticated analyses can be conducted by combining multiple bedtools operations on the UNIX command line.

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Knockout Mouse Project Repository (tool)

RRID:SCR_007318

Repository of mouse vectors, ES cells, mice, embryos, and sperm generated by NIH KOMP Mutagenesis Project. In addition, KOMP Repository offers services in support of KOMP products, including ES cell microinjection, vector cloning, post-insertional modification of cloned ES cells, cryopreservation, assisted reproduction techniques (IVF, ICSI) and mouse breeding, pathology services, phenotyping services, etc. KOMP Repository is final component of more than $50 million trans-NIH initiative to increase availability of genetically altered mice and related materials. The University of California, Davis (UC Davis) and Children''s Hospital Oakland Research Institute (CHORI) in Oakland, Calif., are collaborating to preserve, protect, and make available about 8,500 types of knockout mice and related products available to research community. Products are generated by two KOMP mutagenesis teams (CSD consortium and Regeneron Inc). All KOMP products generated by CSD consortium and Regeneron are available through KOMP Repository. Notice as of December 19, 2019: Materials from KOMP Repository have been deposited into MMRRC, including all mouse models and mouse embryonic stem cell lines. Eventually www.komp.org will be sunsetting, and IMSR will remove KOMP Repository listings, since they were double listed in MMRRC. MMRRC will contain the most accurate and up to date resource models.

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BWA (tool)

RRID:SCR_010910

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DESeq2 (tool)

RRID:SCR_015687

Software package for differential gene expression analysis based on the negative binomial distribution. Used for analyzing RNA-seq data for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates.

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EpCAM antibody [G8.8] (Allophycocyanin) (antibody)

RRID:AB_10677416

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Monoclonal Anti-Ezrin antibody produced in mouse (antibody)

RRID:AB_476955

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PDGFR-alpha (C-20) (antibody)

RRID:AB_631064

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alpha smooth muscle Actin antibody [EPR5368] (antibody)

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Anti-TAGLN/Transgelin antibody (antibody)

RRID:AB_443021

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YAP (D8H1X) XP Rabbit mAb (antibody)

RRID:AB_2650491

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PCNA (PC10) (antibody)

RRID:AB_628110

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C3H/10T1/2 clone 8 (cell line)

RRID:CVCL_0190

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