Just this month we published our latest manuscript in the journal, Frontiers in Cellular Neuroscience, titled, “Genetics studies indicate that neural induction and early neuronal maturation are disturbed in autism.” Even though it’s considered a hypothesis article, it’s actually a semi-quantitative in depth review of the molecular and biological functions of a core set of high risk autism-related genes. The article is available open access so please feel free to download.
As to why we specifically performed this research, we noticed that many neuropathological studies strongly indicate that stages of neurogenesis and early neuronal maturation are disturbed in autism, yet the hot topic in the autism literature on genetics and cell biology tends to focus around the synapse and neurite. Before now, the two groups primarily ignored each other. But the burning question that we asked in this study was, “Are the data from both groups actually correct?” And this manuscript was our answer, to try to bring together these disparate nodes of research under an overarching theory that is complementary rather than confusing.
Here’s what we did: we selected a core set of 197 high-risk autism genes that were comprised of the “Syndromic,” “High Confidence,” and “Strong Candidate” gene lists from the SFARI database and the core and syndromic data sets from AutismKB. Although the trend in current science research is to assess functional overlap between gene products via using large Gene Ontology (GO) networks, which are long lists of keywords with each gene having its own semi-unique constellation, these keywords tend to be overly simplified, are not exhaustive, and therefore information is easily missed. Thus, we went directly to the literature upon which GO data is based. We exhausted the available literature for signs of each gene’s involvement or influence on early stages of maturation in the newborn pre-migratory neuron. This also included the stage preceding and during mitosis known as “neural induction”. We then rated our findings on a 0-3 scale (see the following figure for rating definitions). “3” indicated that there was confirmation of the gene product’s direct involvement in neurogenesis or pre-migratory maturation. Usually this was manifest as premature or suppressed neurogenesis. “0”, on the other hand, indicated that there was no indication of the gene’s involvement in these early maturational stages.
As you can see from the graph, over half of the gene products influenced these very early stages of neuronal maturation. An additional 36% of gene products were strong candidates for involvement in these stages yet could not be directly confirmed via overexpression or knockout studies but protein expression did occur in the early neuroblast or the protein was part of a large pathway that is known to affect early neuronal maturation. Therefore, 88% of these high-risk autism genes are strongly implicated in neural induction, neurogenesis, and early stages of pre-migratory neuronal maturation.
However, we also found that 80% of these gene products also influence later stages of neuronal development, during neurite extension, synapse development, and ongoing plasticity. So it seems, from this study, that both the neuropathologists and geneticists are correct. It’s just that neither has so far proposed a theory that ties the different data together. We’re hoping that this publication is a step in that direction.
We also took a look at these genes’ involvements in epilepsy and schizophrenia. Epilepsy, as probably many of you readers know, is highly comorbid with autism. Approximately 1/3rd will develop a seizure disorder in their lifetimes and meanwhile an additional 1/3rd will exhibit subdiagnostic epileptiform discharges. Schizophrenia, on the other hand, very infrequently co-occurs with either autism or epilepsy (although autistics are more prone to psychotic breaks, just not schizophrenia). At one point in fact, it was believed that epilepsy was a protective factor in schizophrenia and prevented its occurrence; this, however, has been overturned and we now know that schizophrenia and epilepsy occur no more frequently together than at the rate seen in the general population. What we found with our gene list was that approximately 2/3rds were cross-indicated in the etiology of epilepsy; meanwhile, about 1/5th of genes were indicated in schizophrenia.
Following this, we summarized the different functional categories of the gene products present in the list and how each is involved in the various stages of neuronal maturation. Below you can see the list (A), which includes things like calcium regulation, translational regulation, and chromatin remodeling. Overall, we find that each of these specific categories can be lumped into activity-dependent, structure-dependent, product-dependent, and stress-sensitive processes. So, for instance, all stages of neural development are dependent upon excitatory activity. Without that activity, cells fail to proliferate properly, neurons fail to migrate, neurites fail to extend, and synapses fail to develop. These maturational processes are also highly dependent upon the dynamic structure of the cell, such that not only does the cytoskeleton underlie processes of differentiation, it’s also in a constant feedback loop with these systems and can redirect cell fate based upon how it changes. In addition, in order for a cell to differentiate, there must be a shift in some of the gene products it’s producing. This whole process is regulated at numerous levels, through signal transduction, epigenetic changes, transcription regulation, and translation regulation. And finally, activation of the cell stress response can easily alter cell fate determination and disturb neuronal development. If you’re interested in more detailed information on these processes, please read the section on “Convergence Due to Modularity”, which goes into extensive detail with many examples.
So those are our results. We’ve found that gene products strongly indicated in autism risk are involved, not only in later stages of neuronal development such as neurite and synapse formation, but also influence very early stages as well. This is most likely why we see signs of disturbances to neurogenesis and neural fate determination in neuropathological studies on autism, but also disruptions at the dendrite and synapse.
“The culmination of research to date suggests that, though later stages of differentiation are indeed disturbed in autism, encompassing neurite and synapse formation and function, the genesis of these features is generally rooted in even earlier stages of neuronal development and are the result of deviations in cellular identity. Therefore, investigative efforts focusing more holistically on all stages of neuronal development in autism, from progenitor expansion to plasticity, may prove more fruitful than the developmental and morphological compartmentalization that is currently en vogue” (p. 10).