Species-specific FMRP regulation of RACK1 is critical for prenatal cortical development
Summary
Fragile X messenger ribonucleoprotein 1 protein (FMRP) deficiency leads to fragile X syndrome (FXS), an autism spectrum disorder. The role of FMRP in prenatal human brain development remains unclear. Here, we show that FMRP is important for human and macaque prenatal brain development. Both FMRP-deficient neurons in human fetal cortical slices and FXS patient stem cell-derived neurons exhibit mitochondrial dysfunctions and hyperexcitability. Using multiomics analyses, we have identified both FMRP-bound mRNAs and FMRP-interacting proteins in human neurons and unveiled a previously unknown role of FMRP in regulating essential genes during human prenatal development. We demonstrate that FMRP interaction with CNOT1 maintains the levels of receptor for activated C kinase 1 (RACK1), a species-specific FMRP target. Genetic reduction of RACK1 leads to both mitochondrial dysfunctions and hyperexcitability, resembling FXS neurons. Finally, enhancing mitochondrial functions rescues deficits of FMRP-deficient cortical neurons during prenatal development, demonstrating targeting mitochondrial dysfunction as a potential treatment. Copyright © 2023 Elsevier Inc. All rights reserved.
| Authors | Shen M, Sirois CL, Guo Y, Li M, Dong Q, Méndez-Albelo NM, Gao Y, Khullar S, Kissel L, Sandoval SO, Wolkoff NE, Huang SX, Xu Z, Bryan JE, Contractor AM, Korabelnikov T, Glass IA, Doherty D, Birth Defects Research Laboratory, Levine JE, Sousa AMM, Chang Q, Bhattacharyya A, Wang D, Werling DM, Zhao X |
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| Journal | Neuron |
| Publication Date | 2023 Dec 20;111(24):3988-4005.e11 |
| PubMed | 37820724 |
| PubMed Central | PMC10841112 |
| DOI | 10.1016/j.neuron.2023.09.014 |