ArticleDisease models & mechanisms2016
Gli2 gene-environment interactions contribute to the etiological complexity of holoprosencephaly: evidence from a mouse model.
Article in Disease models & mechanisms, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 50 citations in OpenAlex.
- Hedgehog pathway disruption alters urothelial differentiation and continence mechanisms in the female mouse lower urinary tract.American journal of physiology. Renal physiology · 2026Article
- A cell-based Sonic Hedgehog signaling transduction system to identify additive and synergistic chemical interactions.Toxicological sciences : an official journal of the Society of Toxicology · 2026Article
- The Role of the Hedgehog Pathway in Alcohol-Induced Birth Defects.Advances in experimental medicine and biology · 2026Review
- Single-Step Genome-Wide Association Study of Factors for Evaluated and Linearly Scored Traits in Swedish Warmblood Horses.Journal of animal breeding and genetics = Zeitschrift fur Tierzuchtung und Zuchtungsbiologie · 2025Article
- Cranial base synostosis in mice caused by upregulation of Wnt following partial inhibition of Shh.BMC biology · 2025Article
- Role of PROP1 in Postnatal Pituitary Gland Maturation.Endocrinology · 2025Article
- Examining the Neurodevelopmental Impact of Sonic Hedgehog Pathway Inhibition in Mice.Birth defects research · 2025Article
- Examination of piperonyl butoxide developmental toxicity as a Sonic hedgehog pathway inhibitor targeting limb and palate morphogenesis.Reproductive toxicology (Elmsford, N.Y.) · 2024Article
- The impact of the mesoprefrontal dopaminergic system on the maturation of interneurons in the murine prefrontal cortex.Frontiers in neuroscience · 2024Article
- Frem1 activity is regulated by Sonic hedgehog signaling in the cranial neural crest mesenchyme during midfacial morphogenesis.Developmental dynamics : an official publication of the American Association of Anatomists · 2023Article
- High-throughput detection of craniofacial defects in fluorescent zebrafish.Birth defects research · 2023Article
- Gene-alcohol interactions in birth defects.Current topics in developmental biology · 2023Article
- Gene-environment interactions in birth defect etiology: Challenges and opportunities.Current topics in developmental biology · 2023Review
- Lhx2 is a progenitor-intrinsic modulator of Sonic Hedgehog signaling during early retinal neurogenesis.eLife · 2022Article
- Pharmacological activation of the Sonic hedgehog pathway with a Smoothened small molecule agonist ameliorates the severity of alcohol-induced morphological and behavioral birth defects in a zebrafish model of fetal alcohol spectrum disorder.Journal of neuroscience research · 2022Article
- Analysis of Gene-Environment Interactions Related to Developmental Disorders.Frontiers in pharmacology · 2022Review
- FAT4 identified as a potential modifier of orofacial cleft laterality.Genetic epidemiology · 2021Article
- A Microphysiological Approach to Evaluate Effectors of Intercellular Hedgehog Signaling in Development.Frontiers in cell and developmental biology · 2021Article
- Concepts in Multifactorial Etiology of Developmental Disorders: Gene-Gene and Gene-Environment Interactions in Holoprosencephaly.Frontiers in cell and developmental biology · 2021Review
- Identifying environmental risk factors and gene-environment interactions in holoprosencephaly.Birth defects research · 2021Article
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
Abstract
Holoprosencephaly (HPE) is a common and severe human developmental abnormality marked by malformations of the forebrain and face. Although several genetic mutations have been linked to HPE, phenotypic outcomes range dramatically, and most cases cannot be attributed to a specific cause. Gene-environment interaction has been invoked as a premise to explain the etiological complexity of HPE, but identification of interacting factors has been extremely limited. Here, we demonstrate that mutations in Gli2, which encodes a Hedgehog pathway transcription factor, can cause or predispose to HPE depending upon gene dosage. On the C57BL/6J background, homozygous GLI2 loss of function results in the characteristic brain and facial features seen in severe human HPE, including midfacial hypoplasia, hypotelorism and medial forebrain deficiency with loss of ventral neurospecification. Although normally indistinguishable from wild-type littermates, we demonstrate that mice with single-allele Gli2 mutations exhibit increased penetrance and severity of HPE in response to low-dose teratogen exposure. This genetic predisposition is associated with a Gli2 dosage-dependent attenuation of Hedgehog ligand responsiveness at the cellular level. In addition to revealing a causative role for GLI2 in HPE genesis, these studies demonstrate a mechanism by which normally silent genetic and environmental factors can interact to produce severe outcomes. Taken together, these findings provide a framework for the understanding of the extreme phenotypic variability observed in humans carrying GLI2 mutations and a paradigm for reducing the incidence of this morbid birth defect.
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