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PgmNr 139: Identification of human-specific mRNA targets of fragile X mental retardation protein.

Authors:
Y. Li 1; Z. Li 2; Y. Kang 1; E. Allen 1; H. Wu 2; Z. Wen 3; P. Jin 1

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Affiliations:
1) Deptment of Human Genetics, Emory University, Atlanta, GA; 2) Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA Michael St., Atlanta, GA30322; 3) Department of Psychiatrics, Emory University School of Medicine, Atlanta, GA


Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and a leading genetic cause of autism. FXS is caused by the loss of functional fragile X mental retardation protein (FMRP). FMRP is an RNA-binding protein that forms a messenger ribonucleoprotein complex with polyribosomes for the regulation of protein synthesis at synapses. Three-dimensional (3D) aggregate culture of human-induced pluripotent stem cells (iPSCs) has evolved from embryoid body cultures, quite faithfully following human organogenesis, and provides a new platform to investigate human brain development in a dish, otherwise inaccessible to experimentation. We have developed FXS forebrain organoids and observed reduced proliferation of neural progenitor cells, premature neural differentiation and a deficit in the production of GABAergic neurons, findings which were not observed in the FXS mouse model. To identify the mRNAs bound by FMRP, we performed enhanced crosslinking and FMRP immunoprecipitation followed by high-throughput sequencing using human forebrain organoids and mouse embryonic forebrain from similar developmental stages. Our comparative analyses revealed the mRNAs bound by FMRP in both human forebrain organoids and mouse embryonic brains, and they were enriched in mRNAs that are critical for neurodevelopment and axonogenesis. Interestingly, we also identified a large number of mRNAs that were bound by FMRP only in human, and these are enriched in mRNAs that are involved in RNA metabolism and astrocyte differentiation. Furthermore, by overlapping the differentially expressed genes found using RNA-seq in the FXS organoids and human FXS fetal brain tissues, we were able to identify a subset of mRNAs that were bound by FMRP and displayed differential expression in the absence of FMRP specifically in human. Our study has identified human-specific mRNA targets of FMRP, which have the potential to serve as human-specific druggable targets for FXS and autism in general.