Cholesterol and sonic hedgehog signaling in alobar holoprosencephaly

University Of Tennessee Health Sci Ctr, Memphis TN

Investigators

Abstract

Holoprosencephaly (HPE) is the most common congenital forebrain malformation in humans, affecting 1:16,000 live births and causing 1:250 spontaneous abortions. The cardinal feature of HPE is a single telencephalic ventricle with continuity of the cerebral hemisphere across the midline. The phenotype of HPE is variable and proceeds in a continuous spectrum from minimal or no structural brain abnormality to the most severe form, alobar HPE, characterized by the complete failure of the forebrain to divide into left and right halves and is associated with a single ventricle. Although mutations in SHH and in several genes directly involved in the SHH signaling pathway account for a small fraction of HPE cases, they represent approximately 20% of the familial cases of HPE. Cholesterol modification of SHH is essential to restrict its diffusion and ensure proper dorsoventral patterning of the telencephalon. The importance of cholesterol in the etiology of HPE is underscored by the findings that impaired cholesterol biosynthesis and/or transport during embryogenesis leads to HPE in animal models, and that approximately 10% of individuals with HPE have defects in cholesterol biosynthesis. We have found that conditional inactivation of the gene encoding huntigtin (Htt) in the mouse epiblast causes alobar HPE. Furthermore, our preliminary results also show that Htt is essential for cholesterol biosynthesis during embryogenesis. Taken together, our results suggest that Htt plays an essential role in cholesterol-dependent SHH signaling. To address this hypothesis we propose three complementary experimental approaches. Our proposed analyses will be the starting point for further investigating the role of Htt and cholesterol biosynthesis in the etiology of HPE and will not only open a new avenue of research but also provide fundamental information in the mechanisms underlying this common but poorly understood disorder.