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.
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RESEARCH ARTICLE|
06 September 2021
Gene-teratogen interactions influence the penetrance of birth defects by altering Hedgehog signaling strength
Jennifer H. Kong
,
Jennifer H. Kong
1
Departments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, CA 94305
, USA
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Cullen B. Young,
Cullen B. Young
2
Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15201
, USA
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Ganesh V. Pusapati
,
Ganesh V. Pusapati
1
Departments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, CA 94305
, USA
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F. Hernán Espinoza
,
F. Hernán Espinoza
1
Departments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, CA 94305
, USA
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Chandni B. Patel
,
Chandni B. Patel
1
Departments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, CA 94305
, USA
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Francis Beckert,
Francis Beckert
1
Departments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, CA 94305
, USA
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Sebastian Ho
,
Sebastian Ho
2
Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15201
, USA
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Bhaven B. Patel,
Bhaven B. Patel
1
Departments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, CA 94305
, USA
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George C. Gabriel,
George C. Gabriel
2
Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15201
, USA
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L. Aravind
,
L. Aravind
5
National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894
, USA
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J Fernando Bazan
,
J Fernando Bazan
4
ħ bioconsulting llc, Stillwater, MN
, USA
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Teresa M. Gunn
,
Teresa M. Gunn
*
3
McLaughlin Research Institute, Great Falls, MT 59405
, USA
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Cecilia W. Lo
,
Cecilia W. Lo
*
2
Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15201
, USA
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Rajat Rohatgi
1
Departments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, CA 94305
, USA
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Jennifer H. Kong
1
Departments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, CA 94305
, USA
Cullen B. Young
2
Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15201
, USA
Ganesh V. Pusapati
1
Departments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, CA 94305
, USA
F. Hernán Espinoza
1
Departments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, CA 94305
, USA
Chandni B. Patel
1
Departments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, CA 94305
, USA
Francis Beckert
1
Departments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, CA 94305
, USA
Sebastian Ho
2
Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15201
, USA
Bhaven B. Patel
1
Departments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, CA 94305
, USA
George C. Gabriel
2
Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15201
, USA
L. Aravind
5
National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894
, USA
J Fernando Bazan
4
ħ bioconsulting llc, Stillwater, MN
, USA
Teresa M. Gunn
*
3
McLaughlin Research Institute, Great Falls, MT 59405
, USA
Cecilia W. Lo
*
2
Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15201
, USA
1
Departments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, CA 94305
, USA
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Received:
09 Aug 2021
Accepted:
27 Aug 2021
Online ISSN: 1477-9129
Print ISSN: 0950-1991
Funding Group:
- Award Group:
- Funder(s): National Institutes of Health
- Award Id(s): GM118082
- Funder(s):
Funding Group:
- Award Group:
- Funder(s): American Heart Association
- Award Id(s): 14POST20370057
- Funder(s):
Funding Group:
- Award Group:
- Funder(s): U.S. Department of Defense
- Award Id(s): W81XWH-15-1-0649
- Funder(s):
© 2021. Published by The Company of Biologists Ltd
2021
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
Development dev.199867.
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Received:
09 Aug 2021
Accepted:
27 Aug 2021
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Citation
Jennifer H. Kong, Cullen B. Young, Ganesh V. Pusapati, F. Hernán Espinoza, Chandni B. Patel, Francis Beckert, Sebastian Ho, Bhaven B. Patel, George C. Gabriel, L. Aravind, J Fernando Bazan, Teresa M. Gunn, Cecilia W. Lo, Rajat Rohatgi; Gene-teratogen interactions influence the penetrance of birth defects by altering Hedgehog signaling strength. Development 2021; dev.199867. doi: https://doi.org/10.1242/dev.199867
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