Autism spectrum disorders (ASDs) are a group of pervasive neurodevelopment conditions that currently affect 1 in 150 individuals, making ASDs a notable public health issue. Although the cause of ASDs is unknown in the majority of cases, it is known that ASDs affect at least four times as many males as females, and that ASDs are highly heritable, indicating a strong genetic contribution. Continued identification of genes associated with ASDs has advanced our understanding of the role of genetics in ASDs, but the skewed sex ratio in prevalence remains unexplained. To this end, studying a candidate gene that shows sex differences in expression patterns or associated neural phenotypes may provide unique insights into ASD pathophysiology. Data from the Geschwind lab show that cytoplasmic FMRP-interacting protein 1 (CYFIP1) expression patterns are sexually dimorphic, and that neuropathological phenotypes associated with Cyfip1 over-expression may also show sexual dimorphisms, making this candidate gene a unique target for study. CYFIP1 has also been implicated in neural development and function by its interactions with FMRP, the protein silenced in Fragile X Syndrome, and by its involvement in Rac1 signaling and the WAVE complex for regulation of actin remodeling, a process crucial for axon elongation and dendritic development. To further study the function of CYFIP1 in the mammalian nervous system, our lab has engineered a transgenic mouse model that over-expresses Cyfip1. The purpose of the proposed project is to utilize this mouse model to better understand the implications of the sexual dimorphism in Cyfip1 expression in neural development and ASD pathophysiology.
Aim 1 will determine when (at which developmental time points) and where (in which brain regions) sex differences in Cyfip1 expression occur, using quantitative real time PCR and western blotting to assess transcript and protein levels.
Aim 2 will determine which neuronal phenotypes associated with Cyfip1 over-expression are sexually dimorphic by using immunohistochemical and Golgi cell staining techniques to visualize the structure and organization of specific populations of neurons.
Aim 3 will utilize sex steroid hormone manipulation techniques to investigate potential mechanisms driving the sexually dimorphic neuronal phenotypes identified in Aim 2. Together, results from these aims will further our understanding of how perturbations in expression of an autosomal ASD candidate gene can elicit differing effects on neural development in males and females. Continued investigation along these lines will accelerate identification of those factors that cause males to be vulnerable to, or females to be protected from, ASDs, thereby facilitating the development of pharmaceutical treatments and preventive measures for ASDs.

Public Health Relevance

Autism spectrum disorders (ASDs) are neurodevelopment conditions that place significant burden on the families, schools, and support systems of affected children, and although public awareness has increased, the cause of these disorders remains unknown in the vast majority of cases. However, a few features of ASDs are well known: ASDs are highly heritable, indicating a strong genetic contribution to their development, and ASDs affect at least four times as many males as females. Therefore, the study of sex differences associated with an autism candidate gene, CYFIP1, aims to open doors for understanding more about the biological basis for the sex difference in the prevalence of ASDs, while advancing current knowledge about potential causative mechanisms and neurobiological features of ASDs.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F01-L (20))
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Rosemond, Erica K
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University of California Los Angeles
Schools of Arts and Sciences
Los Angeles
United States
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Werling, Donna M; Parikshak, Neelroop N; Geschwind, Daniel H (2016) Gene expression in human brain implicates sexually dimorphic pathways in autism spectrum disorders. Nat Commun 7:10717
Lowe, Jennifer K; Werling, Donna M; Constantino, John N et al. (2015) Social responsiveness, an autism endophenotype: genomewide significant linkage to two regions on chromosome 8. Am J Psychiatry 172:266-75
Werling, Donna M; Geschwind, Daniel H (2013) Sex differences in autism spectrum disorders. Curr Opin Neurol 26:146-53