ArticleThe Journal of clinical investigation2012
Autonomic neurocristopathy-associated mutations in PHOX2B dysregulate Sox10 expression.
Article in The Journal of clinical investigation, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers.
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Who cites it
60 citing papers in PubMed, 104 citations in OpenAlex.
- Association between PHOX2B gene rs28647582 T>C polymorphism and Wilms tumor susceptibility.Bioscience reports · 2019Trial
- Redefining PHOX2B-Related Neurodevelopmental Disorders as Circuitopathies: A New Paradigm in Autonomic Network Medicine.Neuroscience bulletin · 2026Review
- Lessons from In Utero and Postnatal Exposure to Pesticide DDT: Mechanisms of Chromaffin Cell Vulnerability and Altered Catecholamine Homeostasis.International journal of molecular sciences · 2026Review
- Unveiling the Prevalence and Surgical Burden of Neurocristopathies: A Scoping Review and Statistical Analysis.Research square · 2026Article
- Combinatorial multiomic analysis from a pedigree of Sox10Dom Hirschsprung mice identifies multiple high confidence candidate modifiers of Enteric Nervous System development.PLoS computational biology · 2026Article
- Sympathetic Chain Ganglia in the Female Pig During Prenatal Development: Noradrenergic and Cholinergic Neurons.Current issues in molecular biology · 2026Article
- Vinculin influences essential processes in enteric nervous system development and Hirschsprung disease pathogenesis.The Journal of clinical investigation · 2026Article
- CRISPR/Cas9-mediatedFrontiers in physiology · 2026Article
- Combinatorial multiomic analysis from a pedigree of Sox10bioRxiv : the preprint server for biology · 2025Article
- TheFrontiers in physiology · 2025Article
- Molecular Characterization of Nodose Ganglia Development Reveals a Novel Population of Phox2b+ Glial Progenitors in Mice.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- Galaninergic and hypercapnia-activated neuronal projections to the ventral respiratory column.Brain structure & function · 2024Article
- Zebrafish Congenital Heart Disease Models: Opportunities and Challenges.International journal of molecular sciences · 2024Review
- Article
- Generation of Functional and Mature Sympathetic Neurons from Human Pluripotent Stem Cells via a Neuroepithelial Route.Journal of molecular neuroscience : MN · 2024Article
- Article
- Recipient colon preoperative treatment with type I collagenase and fibronectin promotes the growth of transplanted enteric neural crest cells into Auerbach's plexus.Pediatric surgery international · 2022Article
- Molecular ontology of the parabrachial nucleus.The Journal of comparative neurology · 2022Article
- Article
- A Deeper Curse: A Hirschsprung Patient's Evaluation Unmasks a Rare Association with Congenital Central Hypoventilation Syndrome and Neuroblastoma.European journal of pediatric surgery reports · 2022Article
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Authors and funding
10 authors at 4 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The most common forms of neurocristopathy in the autonomic nervous system are Hirschsprung disease (HSCR), resulting in congenital loss of enteric ganglia, and neuroblastoma (NB), childhood tumors originating from the sympathetic ganglia and adrenal medulla. The risk for these diseases dramatically increases in patients with congenital central hypoventilation syndrome (CCHS) harboring a nonpolyalanine repeat expansion mutation of the Paired-like homeobox 2b (PHOX2B) gene, but the molecular mechanism of pathogenesis remains unknown. We found that introducing nonpolyalanine repeat expansion mutation of the PHOX2B into the mouse Phox2b locus recapitulates the clinical features of the CCHS associated with HSCR and NB. In mutant embryos, enteric and sympathetic ganglion progenitors showed sustained sex-determining region Y (SRY) box10 (Sox10) expression, with impaired proliferation and biased differentiation toward the glial lineage. Nonpolyalanine repeat expansion mutation of PHOX2B reduced transactivation of wild-type PHOX2B on its known target, dopamine β-hydroxylase (DBH), in a dominant-negative fashion. Moreover, the introduced mutation converted the transcriptional effect of PHOX2B on a Sox10 enhancer from repression to transactivation. Collectively, these data reveal that nonpolyalanine repeat expansion mutation of PHOX2B is both a dominant-negative and gain-of-function mutation. Our results also demonstrate that Sox10 regulation by PHOX2B is pivotal for the development and pathogenesis of the autonomic ganglia.
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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.