Corticogenesis and Autism Spectrum Disorders: New Hypotheses on Transcriptional Regulation of Embryonic Neurogenesis by FGFs from In Vivo Studies and RNA-sequencing Analysis of Mouse Brain
Autism Spectrum Disorders ASD) are a group of psychiatric conditions characterized by delays in development and pervasive impairment of cognitive abilities, particularly socialization and communication. To date, no treatment has been made available to children with ASD. Dysfunction in the Prefrontal Cortex PFC), particularly in dorsolateral and orbitofrontal subdivisions, has been implicated in the pathophysiology of ASD. Although several lines of evidence suggest that alterations in cortical development may underlie many clinical features of ASD, little is known about molecular mechanisms governing neurogenesis and maturation of PFC neuronal progenitors in ASD. Interestingly, an increased number of neurons in the dorsolateral aspect of PFC has been recently reported in brains from autistic patients with macrocephaly, a key feature in approximately 20% of cases of ASD. We reported that Fibroblast Growth Factors FGFs) and their receptors are required for the regulation of the rate of proliferation of progenitor cells and their differentiation into mature neurons in the neocortex, with FGF receptor 2 being particularly crucial for prelimbic cortex, a subdivision of the mouse PFC. We also recently reported that a single microinjection of FGF2 in mouse cortical primordia before the onset of neurogenesis was sufficient to induce the appearance of bilateral, fully-layered cortical gyri and sulci which persisted through adulthood) in the rostrolateral cortex, a region corresponding to the perspective PFC. Corresponding to FGF2-induced gyrification was increased growth of both the ventricular VZ) and subventricular SVZ) zones, the two proliferative compartments of developing cortex. Conversely, the posterior brain primordium, including the hippocampus, was reduced in size. Interestingly, these effects were not shared by FGF8, another FGF ligand which plays a major role in patterning the brain. Whether i) the appearance of gyri and sulci is molecularly encoded in the developing brain in a region-specific and time-specific manner, ii) which gene networks are specifically modulated by FGFs and how this relates to signaling events elicited by other morphogens, and iii) how these events might impact the processing of executive functions in the mature PFC, still remains largely unknown. Using our already validated next-generation RNA-sequencing pipeline on transcripts selectively extracted from embryonic PFC either treated with FGF2 or FGF8, we aim 1) to reveal the FGF2 and FGF8 specific transcriptomic signatures including splicing variants) and to identify gene networks differentially regulated by FGFs during the development of PFC; 2) to understand how non-coding RNAs, including long-non coding RNAs, micro-RNAs and piwi-RNAs, which account for the vast majority of the transcriptome, regulate neurogenesis and expansion of PFC. There is a growing interest around non-coding RNAs and our preliminary RNA-sequencing data support the notion that micro-RNAs may mediate critical regulatory functions of FGF signaling during brain development. We strongly believe that this strategy, combined with the possibility to validate our findings in vivo, will allow us to gain deeper insights into basic mechanisms of brain growth, may help reveal new critical molecular targets in PFC development and deepen our knowledge to improve both diagnosis and treatment of ASD.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
