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Brain Abnormalities in a Mouse Model for Smith-Lemli-Opitz Syndrome: Implications for Autism

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Session 3: Molecular Genetics of Autism

H Waage-Baudet1,4, JM Lauder1, DB Dehart1,4, K. Kluckman2 J. Piven3, S Tint5 and KK Sulik1,4
1Departments of Cell and Developmental Biology, 2Pathology, 3Psychiatry and 4Bowles Center for Alcohol Research, The University of North Carolina, Chapel Hill NC 27599; and 5VA Hospital, East Orange NJ

Cholesterol biosynthesis is required for normal intrauterine development and defects in various steps of this pathway that yield low cholesterol levels result in birth defects including those that comprise the Smith-Lemli-Opitz Syndrome (SLOS). Individuals with SLOS present with microcephaly, growth and mental retardation, soft tissue syndactyly of the second and third toes, and genital abnormalities. Additionally agenesis of the corpus callosum, frontal lobe hypoplasia, cardiac and lung anomalies, and cleft palate are common findings. Recently, autism has also been reported in approximately 50% of those with a SLOS diagnosis. Mutations in the gene that codes for the enzyme that catalyzes the last step in cholesterol biosynthesis, D7-dehydrocholesterol reductase(DHCR7), are responsible for this syndrome. By mutating this gene in mice, we have created an animal model for SLOS that promises to provide important clues relative to the genesis of autism. Mice homozygous for the mutation ( DHCR7-/-) have low cholesterol and high 7- dehydrocholesterol levels as is typical of SLOS. They die shortly after birth, apparently as a result of lung immaturity. Examination of the brains of perinatal DHCR7-/- animals has illustrated absence of the corpus callosum, with the fibers that should comprise this structure not crossing the midline, but running prependicular to it as Probst bundles. Additionally, the cellular organization of the hippocampus is abnormal. Knowledge of the requirement by key developmental control pathways for sonic hedgehog protein complexed with cholesterol, combined with spatio-temporal maps of genetic pathways dependent on sonic hedgehog provide insight into potential genes and regions that may be key to the genesis of autism. For example, downstream of shh signaling is the netrin-1/DCC system which is important for axon guidance, Examination of changes in this system as it may relate to autism are indicated. Additionally, serotonergic systems are dependent on normal hindbrain floorplate development, an area that requires shh activity. Currently, immunohistochemical analyses are being conducted to investigate potential alterations in the genesis of serotonergic populations in the brains of DHCR7 -/- embryos and fetuses. Preliminary results suggest aberrant development of the rostral and caudal raphe groups. It is hoped that further study of serotonergic neurons in DHCR7-/- mice will help to explain some features of the behavioral phenotype that characterizes autism.

Supported by a grant from the NAAR.

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Last Reviewed: 11/30/2012
Vision National Institutes of Health Home BOND National Institues of Health Home Home Storz Lab: Section on Environmental Gene Regulation Home Machner Lab: Unit on Microbial Pathogenesis Home Division of Intramural Population Health Research Home Bonifacino Lab: Section on Intracellular Protein Trafficking Home Lilly Lab: Section on Gamete Development Home Lippincott-Schwartz Lab: Section on Organelle Biology