Holoprosencephaly (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 the chick 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 SHH pathway. We report that both inhibitors caused HPE-like defects that were dependent on the drug concentration and the developmental stage at the time of treatment. We also investigated double inhibition of NODAL and SHH pathways from the onset of gastrulation 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.
- Received May 3, 2012.
- Accepted November 29, 2012.
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