Gene-teratogen interactions influence the penetrance of birth defects by altering Hedgehog signaling strength

Birth defects result from interactions between genetic and environmental factors, but the mechanisms remain poorly understood. We find that mutations and teratogens interact in predictable ways to cause birth defects by changing target cell sensitivity to Hedgehog (Hh) ligands. These interactions co...

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Published inDevelopment (Cambridge) Vol. 148; no. 19
Main Authors Kong, Jennifer H, Young, Cullen B, Pusapati, Ganesh V, Espinoza, F Hernán, Patel, Chandni B, Beckert, Francis, Ho, Sebastian, Patel, Bhaven B, Gabriel, George C, Aravind, L, Bazan, J Fernando, Gunn, Teresa M, Lo, Cecilia W, Rohatgi, Rajat
Format Journal Article
LanguageEnglish
Published England The Company of Biologists Ltd 01.10.2021
Subjects
Abnormalities, Drug-Induced - genetics
Animals
Cells, Cultured
Gene-Environment Interaction
Hedgehog Proteins - metabolism
HEK293 Cells
Humans
Mice
Mice, Inbred C57BL
NIH 3T3 Cells
Penetrance
Signal Transduction
Smoothened Receptor - genetics
Smoothened Receptor - metabolism
Gene-environment interactions
Structural birth defects
Hedgehog signaling
Smoothened
Morphogen
Left-right patterning
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Abstract Birth defects result from interactions between genetic and environmental factors, but the mechanisms remain poorly understood. We find that mutations and teratogens interact in predictable ways to cause birth defects by changing target cell sensitivity to Hedgehog (Hh) ligands. These interactions converge on a membrane protein complex, the MMM complex, that promotes degradation of the Hh transducer Smoothened (SMO). Deficiency of the MMM component MOSMO results in elevated SMO and increased Hh signaling, causing multiple birth defects. In utero exposure to a teratogen that directly inhibits SMO reduces the penetrance and expressivity of birth defects in Mosmo-/- embryos. Additionally, tissues that develop normally in Mosmo-/- embryos are refractory to the teratogen. Thus, changes in the abundance of the protein target of a teratogen can change birth defect outcomes by quantitative shifts in Hh signaling. Consequently, small molecules that re-calibrate signaling strength could be harnessed to rescue structural birth defects.
AbstractList Birth defects result from interactions between genetic and environmental factors, but the mechanisms remain poorly understood. We find that mutations and teratogens interact in predictable ways to cause birth defects by changing target cell sensitivity to Hedgehog (Hh) ligands. These interactions converge on a membrane protein complex, the MMM complex, that promotes degradation of the Hh transducer Smoothened (SMO). Deficiency of the MMM component MOSMO results in elevated SMO and increased Hh signaling, causing multiple birth defects. In utero exposure to a teratogen that directly inhibits SMO reduces the penetrance and expressivity of birth defects in Mosmo −/− embryos. Additionally, tissues that develop normally in Mosmo −/− embryos are refractory to the teratogen. Thus, changes in the abundance of the protein target of a teratogen can change birth defect outcomes by quantitative shifts in Hh signaling. Consequently, small molecules that re-calibrate signaling strength could be harnessed to rescue structural birth defects. Summary: The MMM complex is a module that attenuates Hedgehog signaling, regulating left-right asymmetry of organs as well as patterning and morphogenesis of multiple tissues in the embryo.
ABSTRACT Birth defects result from interactions between genetic and environmental factors, but the mechanisms remain poorly understood. We find that mutations and teratogens interact in predictable ways to cause birth defects by changing target cell sensitivity to Hedgehog (Hh) ligands. These interactions converge on a membrane protein complex, the MMM complex, that promotes degradation of the Hh transducer Smoothened (SMO). Deficiency of the MMM component MOSMO results in elevated SMO and increased Hh signaling, causing multiple birth defects. In utero exposure to a teratogen that directly inhibits SMO reduces the penetrance and expressivity of birth defects in Mosmo−/− embryos. Additionally, tissues that develop normally in Mosmo−/− embryos are refractory to the teratogen. Thus, changes in the abundance of the protein target of a teratogen can change birth defect outcomes by quantitative shifts in Hh signaling. Consequently, small molecules that re-calibrate signaling strength could be harnessed to rescue structural birth defects.
Birth defects result from interactions between genetic and environmental factors, but the mechanisms remain poorly understood. We find that mutations and teratogens interact in predictable ways to cause birth defects by changing target cell sensitivity to Hedgehog (Hh) ligands. These interactions converge on a membrane protein complex, the MMM complex, that promotes degradation of the Hh transducer Smoothened (SMO). Deficiency of the MMM component MOSMO results in elevated SMO and increased Hh signaling, causing multiple birth defects. In utero exposure to a teratogen that directly inhibits SMO reduces the penetrance and expressivity of birth defects in Mosmo-/- embryos. Additionally, tissues that develop normally in Mosmo-/- embryos are refractory to the teratogen. Thus, changes in the abundance of the protein target of a teratogen can change birth defect outcomes by quantitative shifts in Hh signaling. Consequently, small molecules that re-calibrate signaling strength could be harnessed to rescue structural birth defects.
Author Espinoza, F Hernán
Young, Cullen B
Patel, Bhaven B
Aravind, L
Rohatgi, Rajat
Bazan, J Fernando
Patel, Chandni B
Gunn, Teresa M
Gabriel, George C
Kong, Jennifer H
Pusapati, Ganesh V
Beckert, Francis
Ho, Sebastian
Lo, Cecilia W
AuthorAffiliation 3 National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health , Bethesda, MD 20894 , USA
4 H Bioconsulting , Stillwater, MN 50082, USA
1 Departments of Biochemistry and Medicine , Stanford University School of Medicine , Stanford, CA 94305 , USA
5 McLaughlin Research Institute , Great Falls, MT 59405 , USA
2 Department of Developmental Biology , University of Pittsburgh School of Medicine , Pittsburgh, PA 15201 , USA
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– name: 3 National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health , Bethesda, MD 20894 , USA
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CitedBy_id crossref_primary_10_1080_19490976_2023_2221093
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Issue 19
Keywords Gene-environment interactions
Structural birth defects
Hedgehog signaling
Smoothened
Morphogen
Left-right patterning
Language English
License 2021. Published by The Company of Biologists Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
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  article-title: Staining Whole Mouse Embryos for β-Galactosidase (lacZ) Activity
  publication-title: Cold Spring Harb. Protoc.
  doi: 10.1101/pdb.prot4725
  contributor:
    fullname: Nagy
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Snippet Birth defects result from interactions between genetic and environmental factors, but the mechanisms remain poorly understood. We find that mutations and...
ABSTRACT Birth defects result from interactions between genetic and environmental factors, but the mechanisms remain poorly understood. We find that mutations...
SourceID pubmedcentral
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pubmed
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Index Database
SubjectTerms Abnormalities, Drug-Induced - genetics
Animals
Cells, Cultured
Gene-Environment Interaction
Hedgehog Proteins - metabolism
HEK293 Cells
Humans
Mice
Mice, Inbred C57BL
NIH 3T3 Cells
Penetrance
Signal Transduction
Smoothened Receptor - genetics
Smoothened Receptor - metabolism
Title Gene-teratogen interactions influence the penetrance of birth defects by altering Hedgehog signaling strength
URI https://www.ncbi.nlm.nih.gov/pubmed/34486668
https://pubmed.ncbi.nlm.nih.gov/PMC8513608
Volume 148
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