Wnt signaling networks in autism spectrum disorder and intellectual disability

Abstract

BackgroundGenetic factors play a major role in the risk for neurodevelopmental disorders such as autism spectrum disorders (ASDs) and intellectual disability (ID). The underlying genetic factors have become better understood in recent years due to advancements in next generation sequencing. These studies have uncovered a vast number of genes that are impacted by different types of mutations (e.g., de novo, missense, truncation, copy number variations).AbstractGiven the large volume of genetic data, analyzing each gene on its own is not a feasible approach and will take years to complete, let alone attempt to use the information to develop novel therapeutics. To make sense of independent genomic data, one approach is to determine whether multiple risk genes function in common signaling pathways that identify signaling “hubs” where risk genes converge. This approach has led to multiple pathways being implicated, such as synaptic signaling, chromatin remodeling, alternative splicing, and protein translation, among many others. In this review, we analyze recent and historical evidence indicating that multiple risk genes, including genes denoted as high-confidence and likely causal, are part of the Wingless (Wnt signaling) pathway. In the brain, Wnt signaling is an evolutionarily conserved pathway that plays an instrumental role in developing neural circuits and adult brain function.ConclusionsWe will also review evidence that pharmacological therapies and genetic mouse models further identify abnormal Wnt signaling, particularly at the synapse, as being disrupted in ASDs and contributing to disease pathology.

Alterations in neuronal physiology, development, and function associated with a common duplication of chromosome 15 involvingCHRNA7

“…The AP model exhibited downregulation of a suite of genes involved in integrin signaling, including ITGA1, ITGA2, ITGA3, ITGA5, ITGA9, ITGB3, ITGB4, and ITGB5. Wnt signaling also plays major roles in controlling neuronal proliferation, differentiation, and migration during neurodevelopment, and has recently been shown to be frequently disrupted in ASD (55)(56)(57). As a proposed contributor to ASD disease etiology, a treatment option currently being explored to reduce behavioral deficits and ameliorate brain structural abnormalities involves use of pharmacological modulators of WNT signaling (19,55,58).…”

“…Wnt signaling also plays major roles in controlling neuronal proliferation, differentiation, and migration during neurodevelopment, and has recently been shown to be frequently disrupted in ASD (55)(56)(57). As a proposed contributor to ASD disease etiology, a treatment option currently being explored to reduce behavioral deficits and ameliorate brain structural abnormalities involves use of pharmacological modulators of WNT signaling (19,55,58). Here, we identified 17 differentially regulated WNT signaling-related genes in transcriptomic comparisons between the AP vs UM and Formation of synaptic circuits involves multiple steps, including axonal guidance, neurite outgrowth, growth cone targeting, and synapse formation and maturation (53,61).…”

“…Furthermore, Wnt signaling can contribute to neuronal migration, and we found that the Wnt agonist CHIR-99021 could partially rescue this migration deficit. Modulating Wnt signaling has been explored as an option for ASD treatment; however, as both reduced and elevated Wnt activity have been implicated in ASD-related behavioral and cognitive alterations, further studies are required to stratify how Wnt pathway biomarkers are altered in IDDs including ASD (55)(56)(57).…”

Transcriptional signatures of participant-derived neural progenitor cells and neurons implicate altered Wnt signaling in Phelan McDermid syndrome and autism

“…Notably, many under-expressed genes in the current dataset show enrichment for both Wnt signaling genes and CHD8 binding sites. Both PTEN and TCF7L2 also represent ASD and ID risk genes [58, 60, 86, 87], respectively, and have been identified to function with CTNNB1 to regulate normal brain growth [88] and to initiate transcriptional responses following Wnt receptor binding [89]. Additionally, de novo mutations in DDX3X are associated with ID and ASD [90], and this gene has been recently identified to be an important component of CTNNB1 -mediated Wnt signaling by regulating kinase activity, which in turn promote phosphorylation of Dvl and represents a major hub in the Wnt pathway [91].…”

Disruption of Neurosynaptic Physiology and Neuron Network Dysfunction in Brain Disorders: An Environmental and Occupational Health Perspective

“…Neurodegenerative diseases as AD, PD and huntington's disease involve gradual neuronal death leading to decline in movement control, memory and cognition. Autism Spectrum Disorders (ASD), are diagnosed before 2 nd to 3 rd year of age i.e., the period of synapse formation and maturation in humans [156]. Alzheimer's disease is charecterised by loss of neurons and synapses in hippocampus, cerebral cortex and subcortical regions.…”