Transcriptional Dysregulation of Neocortical Circuit Assembly in ASD

Abstract

Autism spectrum disorders (ASD) impair social cognition and communication, key higher order functions centered in the human neocortex. The assembly of neocortical circuitry is a precisely regulated developmental process susceptible to genetic alterations that can ultimately affect cognitive abilities. Because ASD is an early onset neurodevelopmental disorder that disrupts functions executed by the neocortex, miswiring of neocortical circuits has been hypothesized to be an underlying mechanism of ASD. This possibility is supported by emerging genetic findings and data from imaging studies. Recent research on neocortical development has identified transcription factors (TFs) as key determinants of neocortical circuit assembly, mediating diverse processes including neuronal specification, migration, and wiring. Many of these TFs (TBR1, SOX5, FEZF2, and SATB2) have been implicated in ASD. Here, I will discuss the functional roles of these transcriptional programs in neocortical circuit development and their neurobiological implications for the emerging etiology of ASD.

Corticothalamic Projection Neuron Development beyond Subtype Specification: Fog2 and Intersectional Controls Regulate Intraclass Neuronal Diversity

“…Abnormal assembly of cortical circuits is hypothesized to underlie many neurodevelopmental disorders such as cognitive disability, autism spectrum disorders, epilepsy, schizophrenia, and ADHD (Kwan 2013, Mitchell 2011). Here, we report that, in the absence of Fog2 function, CThPN circuitry is abnormal in the prefrontal and motor cortex.…”

Optimizing neuronal differentiation from induced pluripotent stem cells to model ASD

“…This is especially important for hPSC-based ASD modeling, as abnormal neocortical development has been directly associated with the etiology of some ASDs (Kwan, 2013). Thus, we first give an overview of neuronal composition in the neocortex and its origins, based on the studies of animal models.…”

Approaching motor and language deficits in autism from below: a biolinguistic perspective

“…Similarly, one finds several candidates for ASD among the genes comprising the second set, centered on the FOXP2 / ROBO1 interactomes, including ROBO2 (Suda et al, 2011 ), FOXP1 (Hamdan et al, 2010 ), POU3F2 (Lin et al, 2011 ), and CNTNAP2 (Alarcón et al, 2008 ). Finally, AUTS2 (Oksenberg and Ahituv, 2013 ) is a robust candidate for ASD, and this is also the case with other genes that are functionally linked to it, like TBR1 (Deriziotis et al, 2014 ), FEZF2 (Wang et al, 2009 ), PAX6 (Maekawa et al, 2009 ) and SATB2 (Kwan, 2013 ).…”