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.
Gene-teratogen interactions influence the penetrance of birth defects by altering Hedgehog signaling strength
Lead Contact
- Award Group:
- Funder(s): National Institutes of Health
- Award Id(s): GM118082
- Funder(s):
- Award Group:
- Funder(s): American Heart Association
- Award Id(s): 14POST20370057
- Funder(s):
- Award Group:
- Funder(s): U.S. Department of Defense
- Award Id(s): W81XWH-15-1-0649
- Funder(s):
Currently Viewing Accepted Manuscript - Newer Version Available
- Split-screen
- Views Icon Views
-
Article Versions Icon
Versions
- Version of Record 04 October 2021
- Accepted Manuscript 06 September 2021
- Share Icon Share
-
Tools Icon
Tools
- Search Site
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
Download citation file:
Advertisement
Pathway to Independence programme

We’re excited to announce our new Pathway to Independence programme, aimed at supporting postdocs as they go on the job market. Find out more about the scheme in our Editorial.
Call for papers: Metabolic and Nutritional Control of Development and Regeneration

We are welcoming submissions for our next special issue, which will focus on metabolic and nutritional control of development and regeneration. Submission deadline: 15 May 2023.
Webinar: Increasing the visibility and impact of your research
-HUBSwebinar.jpg?versionId=4486)
Would you like to increase the visibility and impact of your research and raise your profile internationally? If so, register for the very practical webinar we are running in association with HUBS on 23 February 2023.
Transitions in development: Daniel Grimes

Daniel Grimes’s lab studies the consequences of ciliary mutations, including left-right patterning defects and scoliosis. We interviewed Daniel to find out more about his career path, his experience of becoming a group leader and the influence of Jurassic Park.
Preprints in Development
(update)-InPreprints.png?versionId=4486)
As part of our efforts to support the use of preprints and help curate the preprint literature, we are delighted to launch a new article type: ‘In preprints’. These pieces will discuss one or more recent preprints and place them in a broader context.