C9orf72 is essential for neurodevelopment and motility mediated by cyclin G1.

C9orf72 is essential for neurodevelopment and motility mediated by cyclin G1.
Exp Neurol. 2018 Mar 06;:
Authors: Yeh TH, Liu HF, Li YW, Lu CS, Shih HY, Chiu CC, Lin SJ, Huang YC, Cheng YC
Abstract
Hexanucleotide repeat expansions in the C9orf72 gene are a common genetic cause of familial and sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, the function of C9orf72 in neural development and the pathogenic mechanism underlying neurodegeneration are unknown. We found that disrupting C9orf72 expression by using C9orf72 constructs that lack the complete DENN domain result in reduced GTPase activity in zebrafish embryos, demonstrating the indispensability of the complete DENN domain. This effect was phenocopied by knocking down endogenous C9orf72 expression by using morpholinos. C9orf72-deficient zebrafish embryos exhibited impaired axonogenesis and motility defects. The C9orf72 deficiency upregulated the expression of tp53 and caused neuronal apoptosis. Knockdown Tp53 in the C9orf72-deficient embryos rescued only the apoptotic phenotype but not the phenotype with axonal and motility defects. The C9orf72 deficiency also induced ccng1 (encodes Cyclin G1) mRNA expression, and injection of a dominant-negative Cyclin G1 construct rescued the axonal impairment, apoptosis, and motility defects in the C9orf72-deficient embryos. Our results revealed the GTPase activity of C9orf72 and demonstrated that Cyclin ...

Source: Experimental Neurology - March 6, 2018 Category: Neurology Authors: Yeh TH, Liu HF, Li YW, Lu CS, Shih HY, Chiu CC, Lin SJ, Huang YC, Cheng YC Tags: Exp Neurol Source Type: research