Related Experiment Video
Updated: Jul 30, 2026
Induction of Protein Deletion Through In Utero Electroporation to Define Deficits in Neuronal Migration in Transgenic Models
Published on: January 12, 2015
Species-specific FMRP regulation of RACK1 is critical for prenatal cortical development
Minjie Shen1, Carissa L Sirois1, Yu Guo1
1Waisman 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.
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.
Insights
Fragile X messenger ribonucleoprotein 1 protein (FMRP) deficiency impairs prenatal brain development, causing mitochondrial issues and hyperexcitability. Enhancing mitochondrial function may treat fragile X syndrome (FXS).
Area of Science:
- Neuroscience
- Developmental Biology
- Genetics
Background:
- Fragile X syndrome (FXS), an autism spectrum disorder, is caused by Fragile X messenger ribonucleoprotein 1 protein (FMRP) deficiency.
- The precise role of FMRP in prenatal human brain development is not fully understood.
Purpose of the Study:
- To investigate the role of FMRP in human and macaque prenatal brain development.
- To identify molecular mechanisms underlying FMRP deficiency in neurons.
Main Methods:
- Utilized human fetal cortical slices and patient-derived stem cells.
- Performed multiomics analyses to identify FMRP-bound mRNAs and interacting proteins.
- Investigated the function of RACK1 and mitochondrial enhancement in neuronal models.
Main Results:
- FMRP deficiency in neurons leads to mitochondrial dysfunction and hyperexcitability.
- Identified novel FMRP targets and interactions, revealing a role in regulating essential prenatal developmental genes.
- Demonstrated that FMRP interaction with CNOT1 maintains RACK1 levels, and RACK1 reduction mimics FXS neuronal deficits.
- Showed that enhancing mitochondrial function rescues prenatal neuronal deficits in FMRP-deficient models.
Conclusions:
- FMRP is crucial for prenatal brain development, regulating essential genes.
- Mitochondrial dysfunction and hyperexcitability are key features of FMRP deficiency.
- Targeting mitochondrial dysfunction presents a potential therapeutic strategy for FXS.
