Interrogate FMRP functions in primate brain development - Fragile X Syndrome (FXS), caused by deficiency of RNA binding protein Fragile X Messenger Ribonucleoprotein 1 protein (FMRP), encoded by X-linked FMR1 gene, is the most common heritable cause of intellectual disability and a top contributor to autism spectrum disorders (ASD). The mechanisms underlying FXS are not fully clear. Our knowledge of FMRP functions in the mammalian brain are mostly obtained from rodent studies. However, there are significant differences between primate and rodent brains, particularly in the prefrontal cortex (PFC) where FMRP is highly expressed. PFC is critical for myriad higher-order brain functions, such as working memory, planning, decision-making, language, and creative intelligence, which are severely affected in FXS. Primate PFC is significantly larger proportionally and much more complex compared to other species and exhibit gene signatures unique to primates. To date, clinical trials based on rodent models have not achieved primary endpoints highlighting a critical need for complementary primate models to better understand FXS. FMRP binds many mRNAs in the brain. An established role of FMRP is that it promotes neuronal maturation and synaptogenesis during postnatal development,. On the other hand, FMRP is also robustly expressed in human and mouse cortex during prenatal development and its deficiency affects mouse cortical development. In contrast to its well-established role in postnatal brain development and function, the role of FMRP in prenatal brain development is not well studied, especially in primates. In addition, Developmental stage-specific roles of FMRP have not been fully investigated and primate-specific targets of FMRP have not been systematically identified. The goal of this project is to investigate functions of FMRP in primate prenatal brain development and unveil developmental stage-specific roles of FMRP in primate brains. We will test the hypothesis that FMRP regulates genes critical for functional maturation of PFC neurons, and its deficiency leads to altered gene expression and impaired cortical development. We determine the impact of FMRP-deficiency on gene expression changes that impair neuronal maturation during primate prenatal development using Patch-seq. We will identify FMRP-mRNAs and FMRP-protein interactomes in the PFC that regulate primate brain development using CLIP-seq and Co-IP-mass spectrometry, respectively. The proposed work will fill a major gap of our knowledge in understanding function of FMRP in primate brain development. Such understanding is critical for better therapeutic development for FXS as well as other neurodevelopmental disorders including ASD.
