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[P2.58]: Modeling the functional genomics of autism using human neurons
Author(s) -
Konopka G.,
Wexler E.
Publication year - 2010
Publication title -
international journal of developmental neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.761
H-Index - 88
eISSN - 1873-474X
pISSN - 0736-5748
DOI - 10.1016/j.ijdevneu.2010.07.188
Subject(s) - citation , autism , library science , human memory , cognitive science , computer science , psychology , neuroscience , psychiatry , cognition
Autism is one of the most common neurodevelopmental disorders, yet the etiology of the disease remains unknown. Genetic association studies have begun to provide insight into key molecules involved in both autism and the broader autism spectrum disorder (ASD). However, disruption of these candidate genes can only explain the pathology of a small fraction of the total number of affected individuals. A likely explanation for uncovering few monogenetic causes of autism is that the disease is caused by the combination of multiple genetic insults coupled to environmental modifiers. Therefore, current animal models are not sufficiently complex enough to completely mimic the etiology of ASD. In addition, the specific disruption to higher cognition, such as language and social reciprocity, in patients with autism presents a challenge for interpretation of data from non-human systems. To address these difficulties, we examined whether a human neuronal culture system could be utilized in modeling some of the more complex genetic features of autism. These normal human neuronal progenitors (NHNPs) were differentiated into a post-mitotic neuronal state through addition of specific growth factors. We examined whole genome gene expression throughout a time course of differentiation. After 4 weeks of differentiation, the cells displayed both morphological features and gene expression patterns indicative of a neuronal fate. Strikingly, a significant number of genes associated with ASD are either induced or repressed at this time point compared to undifferentiated cells. Moreover, we find a significant percentage of ASD genes highly connected to one another during the differentiation process using an unbiased assessment of underlying gene expression connectivity. Finally, the NHNP cells are genetically tractable, allowing for the manipulation of multiple candidate genes simultaneously or the administration of numerous environmental hazards. Thus, NHNPs can be used to study both the effects of mutation of several ASD candidate genes on neuronal differentiation gene expression and the effects of extracellular molecules. These data should provide us with a better understanding of the signaling pathways disrupted in ASD.