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

Jennifer H Kong,J Fernando Bazan,George C Gabriel,Teresa M Gunn,Chandni B Patel,Francis Beckert,Cullen B Young,F Hernán Espinoza,Rajat Rohatgi,Sebastian Ho,Ganesh V Pusapati,L Aravind,Cecilia W Lo,Bhaven B Patel

doi:10.1242/dev.199867

Abstract

ABSTRACTBirth 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.

Highlights

Six percent of newborns suffer from structural birth defects, leading to 8 million cases per year worldwide (Christianson et al, 2005)
MOSMO is required for embryonic development Mosmo is a previously unannotated gene we initially identified in a loss-of-function CRISPR screen conducted in NIH/3T3 fibroblasts designed to find negative attenuators of Hh signaling (Pusapati et al, 2018)
Mosmo−/− phenotypes are correlated with elevated Hh signaling activity To understand the etiology of the birth defects observed in Mosmo−/− embryos, we focused on the Hh signaling pathway because Mosmo was originally identified as an attenuator of Hh signaling in our CRISPR screens (Pusapati et al, 2018), and many of the Mosmo−/− phenotypes can be caused by elevated Hh signaling (Hui and Joyner, 1993)

Summary

Introduction

Six percent of newborns suffer from structural birth defects, leading to 8 million cases per year worldwide (Christianson et al, 2005). Many of these structural defects require surgical intervention early in life and lead to adverse long-term health consequences. The underlying mechanisms driving birth defects remain unknown in a majority of cases. In most cases the specific molecular mechanisms remain poorly understood. Penetrance and expressivity of birth defects, both between embryos and between tissues, remains unpredictable and confounds identification of causal factors. Improved understanding of molecular mechanisms is crucial to developing strategies to alleviate the significant public health burden of birth defects

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Conclusion