ArticlePLoS genetics2012
A mouse model of acrodermatitis enteropathica: loss of intestine zinc transporter ZIP4 (Slc39a4) disrupts the stem cell niche and intestine integrity.
Article in PLoS genetics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 71 papers.
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Who cites it
71 citing papers in PubMed, 144 citations in OpenAlex.
- A Narrative Review of Zinc Deficiency-Associated Anemia.Hematology reports · 2026Review
- Integrating physicochemical and microbial characterization of red rice broth fermented over an 18-hour period augmented with metagenomic and metabolomic approaches.RSC advances · 2026Article
- Paneth cells as orchestrators of epithelial barrier defense and emerging therapeutic targets in inflammatory bowel disease.Seminars in immunopathology · 2026Review
- Understanding molecular mechanisms driving cadmium-induced mitochondrial dysfunction in human metabolic liver disease.Environmental toxicology and pharmacology · 2026Review
- Pathophysiological significance of impaired KAT7-dependent histone H3K14 acetylation during zinc deficiency.Nature communications · 2026Article
- Association of Higher Intakes of Dietary Zinc with Higher Ferritin or Hemoglobin: a Cross-sectional Study from NHANES (2017-2020).Biological trace element research · 2025Article
- Zinc Alleviates Gut Barrier Dysfunction by Promoting the Methylation of AKT.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Advances in intestinal epithelium and gut microbiota interaction.Frontiers in microbiology · 2025Review
- Roles of zinc and zinc transporters in development, progression, and treatment of inflammatory bowel disease (IBD).Frontiers in nutrition · 2025Review
- Supplementation of zinc-chelating peptides fromFrontiers in nutrition · 2025Article
- Impact of zinc oxide on gut health, immunity, and growth in weaned piglets: exploring potential modes of action.Frontiers in veterinary science · 2025Article
- Identification and Characterization of Multiple Paneth Cell Types in the Mouse Small Intestine.Cells · 2024Article
- Cbl and Cbl-b ubiquitin ligases are essential for intestinal epithelial stem cell maintenance.iScience · 2024Article
- Exploring the Interplay between the Hologenome and Complex Traits in Bovine and Porcine Animals Using Genome-Wide Association Analysis.International journal of molecular sciences · 2024Article
- Intestinal inflammation marker calprotectin regulates epithelial intestinal zinc metabolism and proliferation in mouse jejunal organoids.Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2024Article
- Pharmacological Activation of TRPC6 Channel Prevents Colitis Progression.International journal of molecular sciences · 2024Article
- Cellular zinc metabolism and zinc signaling: from biological functions to diseases and therapeutic targets.Signal transduction and targeted therapy · 2024Review
- Research progress on the molecular structure, function, and application in tumor therapy of zinc transporter ZIP4.International journal of biological sciences · 2024Review
- Psoralen synergies with zinc implants to promote bone repair by regulating ZIP4 in rats with bone defect.Biomaterials research · 2023Article
- Metal transporter SLC39A14/ZIP14 modulates regulation between the gut microbiome and host metabolism.American journal of physiology. Gastrointestinal and liver physiology · 2023Article
11 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Mutations in the human Zip4 gene cause acrodermatitis enteropathica, a rare, pseudo-dominant, lethal genetic disorder. We created a tamoxifen-inducible, enterocyte-specific knockout of this gene in mice which mimics this human disorder. We found that the enterocyte Zip4 gene in mice is essential throughout life, and loss-of-function of this gene rapidly leads to wasting and death unless mice are nursed or provided excess dietary zinc. An initial effect of the knockout was the reprogramming of Paneth cells, which contribute to the intestinal stem cell niche in the crypts. Labile zinc in Paneth cells was lost, followed by diminished Sox9 (sex determining region Y-box 9) and lysozyme expression, and accumulation of mucin, which is normally found in goblet cells. This was accompanied by dysplasia of the intestinal crypts and significantly diminished small intestine cell division, and attenuated mTOR1 activity in villus enterocytes, indicative of increased catabolic metabolism, and diminished protein synthesis. This was followed by disorganization of the absorptive epithelium. Elemental analyses of small intestine, liver, and pancreas from Zip4-intestine knockout mice revealed that total zinc was dramatically and rapidly decreased in these organs whereas iron, manganese, and copper slowly accumulated to high levels in the liver as the disease progressed. These studies strongly suggest that wasting and lethality in acrodermatitis enteropathica patients reflects the loss-of-function of the intestine zinc transporter ZIP4, which leads to abnormal Paneth cell gene expression, disruption of the intestinal stem cell niche, and diminished function of the intestinal mucosa. These changes, in turn, cause a switch from anabolic to catabolic metabolism and altered homeostasis of several essential metals, which, if untreated by excess dietary zinc, leads to dramatic weight loss and death.
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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.