RT Journal Article SR Electronic T1 Cdon mutation and fetal alcohol converge on Nodal signaling in a mouse model of holoprosencephaly JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.04.30.070870 DO 10.1101/2020.04.30.070870 A1 Mingi Hong A1 Annabel Christ A1 Anna Christa A1 Thomas E. Willnow A1 Robert S. Krauss YR 2020 UL http://biorxiv.org/content/early/2020/06/24/2020.04.30.070870.abstract AB Holoprosencephaly (HPE), a defect in midline patterning of the forebrain and midface, arises ~1 in 250 conceptions. It is associated with predisposing mutations in the Nodal and Hedgehog (HH) pathways, with penetrance and expressivity graded by genetic and environmental modifiers, via poorly understood mechanisms. CDON is a multifunctional co-receptor, including for the HH pathway. In mice, Cdon mutation synergizes with fetal alcohol exposure, producing HPE phenotypes closely resembling those seen in humans. We report here that, unexpectedly, Nodal, not HH, signaling is the point of synergistic interaction between Cdon mutation and fetal alcohol. Window-of-sensitivity, genetic, and in vitro findings are consistent with a model whereby brief exposure of Cdon mutant embryos to ethanol during gastrulation transiently and partially inhibits Nodal pathway activity, with consequent effects on downstream HH signaling during midline patterning. These results illuminate mechanisms of gene-environment interaction in a multifactorial model of a common birth defect.Competing Interest StatementThe authors have declared no competing interest.