Identification of the embryonic stage when injury can cause autism has led to the insight that the disorder has initiated by changes in the developing brain stem. The shortening of the hindbrain and loss of cranial nerve neurons in an animal model of the insult and a human case of autism resemble features of the Hoxa-1 transgenic knockout mouse. Thus, it is now possible to suggest a unifying hypothesis regarding the multiple etiologies of autism: We propose that teratogens and genetic defects lead to similar developmental changes in the brain stem because mutations of early developmental genes are the cause of familial cases and the teratogens which cause the disease act by interfering with function of the same genes. The new finding that tone of the candidate genes is abnormal in some cases of autism supports this hypothesis. Using mice transgenic for the reporter lac Z, which have been created to signal the level of expression of Hoxa-1, we shall compare the effects of valproic acid (a known cause of autism) and 2-ethyhexanoic acid (a teratogen with similar somatic effects) to the effects of retinoic acid (a teratogen known to interfere with the Hox gene cascade, and now suspected to be cause of autism) on Hox gene expression. In addition, we shall compare the expression of markers on the rhombomeres in embryos from the same litters, using in situ hybridization. In older embryos we shall compare the effects of the three teratogens on the morphology of the developing brain stem, using immunocytochemistry and of traditional serial sectioning with cresyl violet staining to examining the early structure of the cranial nerves, ganglia, and nuclei. We shall mutation mutations of early developmental genes identified in Project III to create a house model of genetically- induced autism, and examined the morphology of the brain stem in transgenic mutants. Subjecting heterozygotes of the genetic model to teratogens will tell us whether teratologic injury can interact with genetic abnormality to alter the brain stem. The animal models developed in this project will be evaluated behaviorally in Project II. The studies of Project I will help us predict which teratogens are likely causes of autism, and further our understanding of the developmental origin of the brain abnormalities associated with the disorder.
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