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Peripheral neuropathy linked mRNA export factor GANP reshapes gene regulation in human motor neurons
- Publication Year :
- 2021
- Publisher :
- Cold Spring Harbor Laboratory, 2021.
-
Abstract
- SUMMARYLoss-of-function of the mRNA export protein GANP (MCM3AP gene) cause early-onset sensorimotor neuropathy, characterised by axonal degeneration in long peripheral nerves. GANP functions as a scaffold at nuclear pore complexes, contributing to selective nuclear export of mRNAs. Here, we aimed to identify motor neuron specific transcripts that are regulated by GANP and may be limiting for local protein synthesis in motor neuron axons. We compared motor neurons with a gene edited mutation in the Sac3 mRNA binding domain of GANP to isogenic controls. We also examined patient-derived motor neurons. RNA sequencing of motor neurons as well as nuclear and axonal subcompartments showed that mutant GANP had a profound effect on motor neuron transcriptomes, with alterations in nearly 40 percent of all expressed genes and broad changes in splicing. Expression changes in multiple genes critical for neuronal functions, combined with compensatory upregulation of protein synthesis and early-stage metabolic stress genes, indicated that RNA metabolism was abnormal in GANP-deficient motor neurons. Surprisingly, limited evidence was found for large-scale nuclear retention of mRNA. This first study of neuropathy-linked GANP defects in human motor neurons shows that GANP has a wide gene regulatory role in a disease-relevant cell type that requires long-distance mRNA transport.
- Subjects :
- Regulation of gene expression
0303 health sciences
Messenger RNA
Motor neuron
Biology
Cell biology
03 medical and health sciences
0302 clinical medicine
medicine.anatomical_structure
nervous system
RNA splicing
Protein biosynthesis
medicine
MRNA transport
Nuclear export signal
Gene
030217 neurology & neurosurgery
030304 developmental biology
Subjects
Details
- Database :
- OpenAIRE
- Accession number :
- edsair.doi...........9c1ce0a7e31db46801d1220721d28531