Genetics Studies Indicate That Disturbances in Premigratory Neuroblast Maturation Are a Core Feature in the Pathology of Autism Spectrum Disorders
Objectives: To address whether high-risk autism gene products affect multiple stages of neuronal development, from neurogenesis and induction, to neurite extension and synaptogenesis, in the hopes of reconciling the range of findings reported in autism.
Methods: Because many studies have relied on simplified Gene Ontology (GO) terms to investigate overlapping biological functions in autism-risk genes, we instead took a more direct approach to understand the various functions that these gene products maintain and what stages of neuronal development are ultimately affected. We did so by scouring the original literature upon which GO terminology has been founded, searching for indications of involvement in neurogenesis and pre-migratory neuronal fate determination. We investigated 197 high-risk syndromic and nonsyndromic autism genes, derived from the SFARI and AutismKB databases, hereto referred as the “core set”. A 0-3 rating scale was used to summarize findings for each gene: “0” indicated that there was no known relationship between the gene product and early neuroblast development, “1” suggested minor evidence, “2” indicated moderate, highly-suggestive evidence for involvement, and “3” indicated a confirmed direct relationship. We also looked for evidence as to whether these same gene products influenced later stages of neuronal development, specifically in neurite elongation, branching, synaptogenesis, and plasticity.
Results: Our review revealed that 88% of the core set attained a rating of 2-3, with 52% of the core gene set directly influencing induction and/or pre-migratory neuroblast differentiation. This was most frequently manifest as premature or delayed neurogenesis in loss-of-function and overexpression studies. Meanwhile, 80% of the core set gene products also influenced later stages of neuronal development, e.g., neuritogenesis and synaptogenesis.
Conclusions: Most high-risk autism gene products influence multiple stages of neuronal development, encompassing induction and neurogenesis, pre-migratory differentiation, migration, axonal and dendritic elongation and branching, synapse formation, and dendritic and synaptic plasticity. This may be due to a combination of cascading effects from earlier foundational stages leading to a reverberation throughout the life of the neuron, as well as functional redundancy of gene products that are reused at multiple stages of neuronal development. This work offers a theoretical construct in which to view the neuropathological and genetics research produced on autism to date under a single umbrella, one which helps to integrate apparently disparate findings into a single pathological concept.