Identification of FMRP target genes expressed during corticogenesis: Implication for common phenotypes among neurodevelopmental disorders

概要

Fragile X mental retardation protein (FMRP) is encoded by fragile X mental retardation 1 (FMR1) gene that is responsible for Fragile X Syndrome (FXS) showing intellectual disability as well as autism spectrum disorder and other symptoms. FMRP is an RNA binding protein highly expressed in the brain. Although several target genes for FMRP have been identified, limited studies have suggested the role of FMRP in corticogenesis. Here I performed RNA immunoprecipitation sequencing against the murine embryonic neocortex, and identified 865 genes as potential mRNA targets of FMRP. I found 124 of these genes as overlapped with autism-related genes, 48 of which were categorized into four functional groups: “transcriptional regulation”, “regulation of actin cytoskeleton”, “ubiquitin-mediated proteolysis” and “calcium signaling pathway”. Four of these 48 genes showed significant difference in expression in the cortical primordium of Fmr1-knockout (Fmr1-KO) mice by quantitative polymerase chain reaction (qPCR); Huwe1 and Kat6a increased, while Kmt2c and Apc decreased. In situ hybridization revealed increased expression of Kat6a and decreased expression of Kmt2c, while no changes in Huwe1 and Apc in the developing cortical primordium. From stability assays using cultured murine astrocytes and embryonic fibroblasts, FMRP seemed to regulate stability of Kmt2c mRNA. Although the change in expression of these four genes was relatively small, these subtle changes due to dysregulated transcription could collectively contribute to impaired corticogenesis to cause phenotypes of FXS. Dysregulation of mRNA stability may also contribute to the development of FXS. Investigating the transcriptional control of FMRP on its mRNA targets may provide new insight to understand neurodevelopmental pathogenesis of FXS.