Cdon mutation and fetal alcohol converge on nodal signaling in a gene-environment interaction model of holoprosencephaly

Item Type:	Preprint
Title:	Cdon mutation and fetal alcohol converge on nodal signaling in a gene-environment interaction model of holoprosencephaly
Creators Name:	Hong, M. and Christ, A. and Christa, A. and Willnow, T.E. and Krauss, R.S.
Abstract:	Holoprosencephaly (HPE), a failure to define the midline of the forebrain and midface, arises in ∼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 that work via poorly understood mechanisms. CDON is a multifunctional co-receptor, including for the HH pathway. In mice, Cdon mutation synergizes with fetal alcohol exposure to produce HPE phenotypes closely resembling those seen in humans. We report here that, unexpectedly, Nodal, not HH, signaling is the point of synergistic interaction between mutation of Cdon and fetal alcohol exposure. A combination of window-of-sensitivity, genetic, and in vitro findings are consistent with a model whereby CDON and another auxiliary receptor, LRP2, function to regulate the Nodal pathway, with consequent effects on downstream HH signaling during midline patterning. Brief exposure of Cdon mutant embryos to ethanol during this period transiently and partially inhibits Nodal pathway activity. These results illuminate mechanisms of gene-environment interaction in a multifactorial model of a common birth defect.
Keywords:	Animals, Mice
Source:	bioRxiv
Title of Book:	Cdon Mutation and Fetal Alcohol Converge on Nodal Signaling in a Gene-Environment Interaction Model of Holoprosencephaly
Publisher:	Cold Spring Harbor Laboratory Press
Article Number:	2020.04.30.070870
Date:	1 May 2020
Official Publication:	https://doi.org/10.1101/2020.04.30.070870

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