Convergence of neurodevelopmental disorder risk genes on common signaling pathways

Abstract

Neurodevelopmental disorders (NDDs) are a heterogeneous set of disorders that are characterized by early disruptions to brain development and include autism spectrum disorder (ASD), attention deficit/hyperactivity disorder (ADHD), developmental delay (DD), intellectual disability (ID), epilepsy and schizophrenia (SZ). Although thousands of genetic risk variants have been identified, there is a lack of understanding of how they impact cellular and molecular mechanisms that underlie the clinical presentation and heterogeneity of NDDs. To investigate this, we used a combination of cellular, molecular, bioinformatic and omics methods to study NDD-associated molecular pathways in distinct neuronal populations. First, we studied the interaction between the high-confidence SZ risk genes DISC1 and NRG1-ErbB4 in cortical inhibitory neurons and found that NRG1-ErbB4 functions through DISC1 to regulate dendrite growth and excitatory synapses onto inhibitory neurons. Next, we studied the 15q13.3 microdeletion, a recurrent copy number variation (CNV) that is associated with multiple NDDs. Using a heterozygous mouse model [Df(h15q13)/+] and human sequencing data we identified OTUD7A (encoding a deubiquitinase) as an important gene driving neurodevelopmental phenotypes in the 15q13.3 microdeletion syndrome. Due to the paucity of literature on the function of OTUD7A in the brain, we used a proximity-labeling approach (BioID2) to elucidate the OTUD7A protein interaction network (PIN) in cortical neurons, and to examine how patient mutations affect the OTUD7A PIN. We found that the OTUD7A PIN was enriched for postsynaptic and axon initial segment proteins, and that distinct patient mutations have shared and distinct effects on the OTUD7A PIN. Further, we identified the interaction of OTUD7A with a high-confidence bipolar risk gene ANK3, which encodes AnkyrinG. We identified decreased levels of AnkyrinG in Df(h15q13)/+ neurons, and synaptic phenotypes were rescued by increasing AnkyrinG levels or targeting the Wnt pathway. Future investigation should include examination of the role of OTUD7A deubiquitinase activity in neural development.