ArticleDevelopment (Cambridge, England)2011
The L6 domain tetraspanin Tm4sf4 regulates endocrine pancreas differentiation and directed cell migration.
Article in Development (Cambridge, England), 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers, 2 of them syntheses that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
27 citing papers in PubMed, 2 syntheses or guidelines pooled it, 38 citations in OpenAlex.
- Genome-wide meta-analysis identifies multiple novel loci associated with serum uric acid levels in Japanese individuals.Communications biology · 2019Pooled it
- Four Susceptibility Loci for Gallstone Disease Identified in a Meta-analysis of Genome-Wide Association Studies.Gastroenterology · 2016Pooled it
- Multi-population genome-wide association meta-analysis of acute and chronic pancreatitis.medRxiv : the preprint server for health sciences · 2026Article
- Multilevel genome-wide analysis reveals shared genetic architecture between acute pancreatitis and body fat distribution.World journal of emergency medicine · 2026Article
- Comparative transcriptomic analysis of endometrial tissue associated with uterine fibroids and endometrial polyps.Scientific reports · 2026Article
- Human pancreatic α-cell heterogeneity and trajectory inference analyses reveal SMOC1 as a β-cell dedifferentiation gene.Nature communications · 2025Article
- Chromatin dynamics and regulatory drivers of hypoplastic hepatic progenitor cells in partial hepatectomy model.Communications biology · 2025Article
- Comparative spatial transcriptomics of pancreatic cancer with ductal and acinar origins in mouse models.Clinical and translational medicine · 2025Article
- MetaQ: fast, scalable and accurate metacell inference via single-cell quantization.Nature communications · 2025Article
- Three Members of Transmembrane-4-Superfamily, TM4SF1, TM4SF4, and TM4SF5, as Emerging Anticancer Molecular Targets against Cancer Phenotypes and Chemoresistance.Pharmaceuticals (Basel, Switzerland) · 2023Review
- Stage-specific transcriptomic changes in pancreatic α-cells after massive β-cell loss.BMC genomics · 2021Article
- Decreased GLUT2 and glucose uptake contribute to insulin secretion defects in MODY3/HNF1A hiPSC-derived mutant β cells.Nature communications · 2021Article
- TM4SF4 and LRRK2 Are Potential Therapeutic Targets in Lung and Breast Cancers through Outlier Analysis.Cancer research and treatment · 2021Article
- Stem cell therapy: a potential for the perils of pancreatitis.The Turkish journal of gastroenterology : the official journal of Turkish Society of Gastroenterology · 2020Review
- Targeting TM4SF5 with anti-TM4SF5 monoclonal antibody suppresses the growth and motility of human pancreatic cancer cells.Oncology letters · 2020Article
- Article
- Gene Signature of the Human Pancreatic ε Cell.Endocrinology · 2018Article
- A radial axis defined by semaphorin-to-neuropilin signaling controls pancreatic islet morphogenesis.Development (Cambridge, England) · 2017Article
- Differential regulation of cellular functions by the C-termini of transmembrane 4 L six family proteins in 2- or 3-dimensional environment.Oncotarget · 2017Article
- Human Pancreatic β Cell lncRNAs Control Cell-Specific Regulatory Networks.Cell metabolism · 2017Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
The homeodomain transcription factor Nkx2.2 is essential for pancreatic development and islet cell type differentiation. We have identified Tm4sf4, an L6 domain tetraspanin family member, as a transcriptional target of Nkx2.2 that is greatly upregulated during pancreas development in Nkx2.2(-/-) mice. Tetraspanins and L6 domain proteins recruit other membrane receptors to form active signaling centers that coordinate processes such as cell adhesion, migration and differentiation. In this study, we determined that Tm4sf4 is localized to the ductal epithelial compartment and is prominent in the Ngn3(+) islet progenitor cells. We also established that pancreatic tm4sf4 expression and regulation by Nkx2.2 is conserved during zebrafish development. Loss-of-function studies in zebrafish revealed that tm4sf4 inhibits α and β cell specification, but is necessary for ε cell fates. Thus, Tm4sf4 functional output opposes that of Nkx2.2. Further investigation of how Tm4sf4 functions at the cellular level in vitro showed that Tm4sf4 inhibits Rho-activated cell migration and actin organization in a ROCK-independent fashion. We propose that the primary role of Nkx2.2 is to inhibit Tm4sf4 in endocrine progenitor cells, allowing for delamination, migration and/or appropriate cell fate decisions. Identification of a role for Tm4sf4 during endocrine differentiation provides insight into islet progenitor cell behaviors and potential targetable regenerative mechanisms.
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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.