Anthony Wynshaw-Boris and his colleagues are investigating the hypothesis that a subset of individuals with autism spectrum disorders (ASD) (approximately 25-30 percent) display early brain overgrowth. His lab has recently produced two relevant models that recapitulate important aspects of early brain overgrowth in ASD. First, the team produced a mouse model deficient for DVL1 and DVL3 (Dvl1/3 +/– mutants). These mice display adult social behavior abnormalities associated with transient embryonic brain enlargement during the time of deep-layer cortical formation[ref]Belinson H. et al. Mol. Psychiatry 21, 1417-1433 (2016) PubMed[/ref]. Second, they generated human induced pluripotent stem cell (iPSC) models by reprogramming fibroblasts obtained from individuals with ASD who had early head overgrowth and unaffected control individuals with normal head circumference. Neuronal progenitor cells (NPCs) derived from ASD iPSC lines displayed enhanced proliferation compared to control NPCs[ref]Marchetto M.C. et al. Mol. Psychiatry Epub ahead of print (2016) PubMed[/ref]. In both the Dvl 1/3 mutant mouse model and the human iPSCs, the observed phenotypes were caused by down-regulation of beta-catenin activity and its direct target BRN2. This remarkable conservation of beta-catenin and BRN2 signaling disruption in different models of ASD suggests that multiple variants contributing to ASD may converge on common pathways.
Aberrant PI3K/PTEN signaling during brain development has emerged as a key determining factor in autism spectrum disorders (ASDs). Germline mutations in PTEN have been found in 20 percent of individuals with ASD and severe macrocephaly. Indeed, there is a growing consensus that deregulation of PI3K/PTEN signaling signifies a convergent pathway for behavioral abnormalities associated with various neurodevelopmental disorders.
Autism spectrum disorder (ASD), affecting 1 in 68 children in the U.S., is a significant unresolved public health concern. The clinical presentations of ASD can be quite broad, and recent evidence points to many different genetic causes. This heterogeneity could lead to a scientific and clinical impasse; each cause of ASD has its own disrupted mechanisms and requires its own unique treatment. However, a more optimistic interpretation, for which there is now accumulating evidence, is that many different primary causes of ASD actually converge on a limited subset of biochemical pathways in nerve cells that mediate cell growth and function. Demonstrating that such a mechanistic convergence exists would be a significant step forward for the field.
Recent studies have provided compelling evidence that loss-of-function mutations in the CHD8 gene, which encodes an ATP-dependent chromatin-remodeling factor, are associated with an autism subtype characterized by macrocephaly, specific craniofacial features and gut immobility. The CHD8 protein modifies the structure of chromatin in the cell nucleus, and in vitro studies have suggested that CHD8 might function as a regulator of the developmentally important Wnt and PTEN signaling pathways. Tight control of both of these pathways is critical for normal brain development, and mutations that affect their activity have been strongly associated with autism and brain size. It is therefore important to test whether CHD8 functions as a regulator of these pathways during brain development.
Copy number variants (CNVs) are the regions of the human genome that represent significant genetic risk factors for autism and other neurodevelopmental disorders. One such CNV located on chromosome 16, called 16p11.2, confers a high risk for developing autism and intellectual disability when deleted, and autism, schizophrenia, bipolar disorder and intellectual disability when duplicated. Even more intriguingly, 16p11.2 deletions are associated with increased head and brain size in the carriers (macrocephaly), whereas 16p11.2 duplications are associated with the decreased head and brain size (microcephaly). However, the exact mechanism by which this CNV influences brain size is unknown.
Abnormal patterns of head and brain growth have been reported in a subset of individuals with autism. A heterogeneous collection of genetic risk factors for autism and micro- and macrocephaly have been identified, including mutations in genes acting in the PI3K-AKT-mTOR (e.g., PTEN) and Wnt-beta-catenin (e.g., CTNNB1, CHD8 and TCF4) signaling pathways.