Species-specific FMRP regulation of RACK1 is critical for prenatal cortical development

Authors: Minjie Shen, Carissa L. Sirois, Yu Guo, Meng Li, Qiping Dong, Natasha M. Méndez-Albelo, Yu Gao, Saniya Khullar, Lee Kissel, Soraya O. Sandoval, Natalie E. Wolkoff, Sabrina X. Huang, Zhiyan Xu, Jonathan E. Bryan, Amaya M. Contractor, Tomer Korabelnikov, Ian A. Glass, Dan Doherty, Birth Defects Research Laboratory, Jon E. Levine, André M.M. Sousa, Qiang Chang, Anita Bhattacharyya, Daifeng Wang, Donna M. Werling, and Xinyu Zhao

CellPress, October 10, 2023

Scientists use the Maestro Pro MEA platform and other methods to explore the association between neurodevelopmental disorders and mitochondrial dysfunction.

Fragile X messenger ribonucleoprotein 1 protein (FMRP) deficiency causes fragile X syndrome FXS—an inherited disorder characterized by intellectual disability and other concerns. FXS is also “the most common single-gene cause of [autism spectrum disorder] ASD.” Previous research has demonstrated that FMRP deficiency is associated with mitochondrial dysfunction, which in turn plays a role in psychiatric and neurodevelopmental disorders [NDDs] including ASD and FXS, but the underlying mechanisms have not been fully understood. In this study, scientists use human fetal cortical slices and FXS patient stem cell-derived neurons to investigate the hypothesis that FMRP regulates essential genes responsible for maintaining neuronal mitochondrial functions during neurodevelopment.

Using Axion’s noninvasive Maestro Pro multielectrode array (MEA) platform and other methods, the researchers confirmed that hypothesis, demonstrating “that FMRP is essential for maintaining mitochondrial functions during human prenatal development by regulating genes whose expression is highest during the early prenatal periods of neurodevelopment (e.g., RACK1) and whose loss of function contributes to NDDs, including ASD.” The authors also showed that enhancing mitochondrial functions rescues deficits associated with FXS, a promising finding that may lead to the development of novel therapeutics.