Abstract
SUMMARYHoloprosencephaly (HPE) is a common congenital defect that results from failed or incomplete forebrain cleavage. HPE is characterized by a wide clinical spectrum, with inter- and intrafamilial variability. This heterogeneity is not well understood and it has been suggested that HPE involves a combination of multiple gene mutations. In this model, several mutated alleles or modifying factors are presumed to act in synergy to cause and determine the severity of HPE. This could explain the various clinical phenotypes. Screening for HPE-associated genes in humans suggests the involvement of NODAL or SHH signaling, or both. To test this multigenic hypothesis, we investigated the effects of chemical inhibition of these two main HPE signaling pathways in a chick embryo model. SB-505124, a selective inhibitor of transforming growth factor-B type I receptors was used to inhibit the NODAL pathway. Cyclopamine was used to inhibit the SHH pathway. We report that both inhibitors caused HPE-like defects that were dependent on the drug concentration and on the developmental stage at the time of treatment. We also investigated double inhibition of NODAL and SHH pathways from the onset of gastrulation by using subthreshold inhibitor concentrations. The inhibitors of the NODAL and SHH pathways, even at low concentration, acted synergistically to promote an HPE-like phenotype. These findings support the view that genetic heterogeneity is important in the etiology of HPE and may contribute to the phenotypic variability.
Highlights
(HPE) is the most common congenital forebrain defect in humans
The authors established a chick embryo culture model to investigate the effects of chemical inhibition of Sonic Hedgehog (SHH) and NODAL pathways during forebrain development
Inactivation of the NODAL signaling pathway from the stage of gastrulation onset leads to severe forebrain defects The chemical inhibitor SB-505124 was used to inactivate NODAL signaling (Hagos and Dougan, 2007)
Summary
(HPE) is the most common congenital forebrain defect in humans. It results from failed or incomplete forebrain cleavage between days 18 and 28 of gestation (Dubourg et al, 2007; Marcorelles and Laquerriere, 2010).The clinical presentation of HPE is remarkably variable, and the severity of the defects observed is evenly distributed along the HPE spectrum. (HPE) is the most common congenital forebrain defect in humans. It results from failed or incomplete forebrain cleavage between days 18 and 28 of gestation (Dubourg et al, 2007; Marcorelles and Laquerriere, 2010). The correlation between the HPE phenotype and genotype is poor, and both sporadic cases and pedigrees display the extensive HPE phenotype variability. This suggests that heterozygous mutations of HPE genes might be insufficient to produce severe anomalies, and that HPE is the consequence of a complex interplay of Received 3 May 2012; Accepted 29 November 2012
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