C9orf72 is essential for neurodevelopment and motility mediated by Cyclin G1

Tu Hsueh Yeh, Han Fang Liu, Yu Wen Li, Chin Song Lu, Hung Yu Shih, Ching Chi Chiu, Sheng Jia Lin, Yin Cheng Huang, Yi Chuan Cheng

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)


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 G1 is an essential downstream mediator for C9orf72 in neural development and motility. Furthermore, downregulating Cyclin G1 was sufficient to rescue all the defects caused by C9orf72 deficiency. In summary, we revealed a novel regulatory mechanism underlying the role of C9orf72 in neurological and motility defects. This result facilitates understanding the function of the C9orf72 gene in the developing nervous system and provides a potential mechanism underlying the pathogenesis of ALS–FTD.

Original languageEnglish
Pages (from-to)114-124
Number of pages11
JournalExperimental Neurology
Publication statusPublished - Jun 1 2018


  • C9orf72
  • Cyclin G1
  • Motility
  • Neurodevelopment
  • Tp53

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience


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