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

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; Xinyu Zhao

doi:10.1016/j.neuron.2023.09.014

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

Neuron. 2023 Dec 20;111(24):3988-4005.e11. doi: 10.1016/j.neuron.2023.09.014. Epub 2023 Oct 10.

Authors

Minjie Shen¹, Carissa L Sirois¹, Yu Guo¹, Meng Li¹, Qiping Dong², Natasha M Méndez-Albelo³, Yu Gao¹, Saniya Khullar⁴, Lee Kissel⁵, Soraya O Sandoval⁶, Natalie E Wolkoff¹, Sabrina X Huang¹, Zhiyan Xu⁷, Jonathan E Bryan⁴, Amaya M Contractor¹, Tomer Korabelnikov¹, Ian A Glass⁸, Dan Doherty⁸; Birth Defects Research Laboratory⁸; Jon E Levine⁹, André M M Sousa¹, Qiang Chang¹⁰, Anita Bhattacharyya¹¹, Daifeng Wang⁴, Donna M Werling¹², Xinyu Zhao¹³

Affiliations

¹ Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA; Department of Neuroscience, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA.
² Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA.
³ Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA; Department of Neuroscience, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA; Molecular Cellular Pharmacology Training Program, University of Wisconsin-Madison, Madison, WI 53705, USA.
⁴ Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA; Departments of Biostatistics and Medical Informatics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA.
⁵ Neuroscience Training Program, University of Wisconsin-Madison, Madison, WI 53705, USA.
⁶ Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA; Department of Neuroscience, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA; Neuroscience Training Program, University of Wisconsin-Madison, Madison, WI 53705, USA.
⁷ Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA; Department of Neuroscience, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA; Graduate Program in Cell and Molecular Biology, University of Wisconsin-Madison, Madison, WI 53705, USA.
⁸ Birth Defects Research Laboratory, University of Washington, Seattle, WA 98195, USA.
⁹ Department of Neuroscience, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA; Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, WI 53715, USA.
¹⁰ Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA; Department of Neurology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA; Laboratory of Genetics, University of Wisconsin-Madison, Madison, WI 53706, USA.
¹¹ Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA; Department of Cell and Regenerative Biology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA.
¹² Laboratory of Genetics, University of Wisconsin-Madison, Madison, WI 53706, USA.
¹³ Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA; Department of Neuroscience, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA. Electronic address: xinyu.zhao@wisc.edu.

PMID: 37820724
PMCID: PMC10841112 (available on 2024-12-20)
DOI: 10.1016/j.neuron.2023.09.014

Abstract

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.

Keywords: FMR1; FMRP interactor; RACK1; ex vivo cortical slices; fragile X syndrome; human specifici physiology; macaque; mitochondria; pluripoent stem cells.

MeSH terms

Autism Spectrum Disorder* / metabolism
Fragile X Mental Retardation Protein / genetics
Fragile X Syndrome*
Humans
Mitochondrial Diseases* / metabolism
Neoplasm Proteins / metabolism
Neurogenesis
Neurons / metabolism
Receptors for Activated C Kinase / genetics
Receptors for Activated C Kinase / metabolism
Transcription Factors / metabolism

Substances

Fragile X Mental Retardation Protein
RACK1 protein, human
Receptors for Activated C Kinase
Neoplasm Proteins
CNOT1 protein, human
Transcription Factors

Abstract

MeSH terms

Substances

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