Aims: Idiopathic congenital nystagmus (ICN) is an oculomotor disorder caused by the defects in the ocular motor control regions of the brain. Mutations in FRMD7, a member of the FERM family of proteins, associated with cytoskeletal dynamics, are the most frequent causes of X-linked ICN. Previous studies illustrated that FRMD7 is involved in the elongation of neurites during neuronal development; however, almost all the studies were performed on mice cell models. The complexity in the human neuronal network might suggest a unique vulnerability of human neurons to FRMD7 mutations.
Methods: Herein, we successfully established human neuronal cell models with FRMD7 mutations, from fibroblasts-reprogrammed neurons (iNs). In these neurons, the complexity of the neuronal processes was measured by the induced ratio, total neurite length, the number of terminals, and the number of maturation neurons.
Results: The complexity of the neuronal processes was greatly reduced during various reprogramming stages in the presence of FRMD7 mutations. Consistently, the expression of the three main Rho GTPases was significantly increased by FRMD7 mutations. Interestingly, a slightly diverse phenotype is observed in different derived neurons.
Conclusion: We established ideal human neuron models and confirmed that the mutation in FRMD7 influences the maturation and complexities of neuronal processes, which might be involved with the Rho GTPase signaling.
Keywords: CRISPR/Cas9; FRMD7; Rho GTPases; idiopathic congenital nystagmus; induced neurons; neuronal outgrowth.
© 2019 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.
Conflict of interest statement
The authors have declared that no competing interests exist.
FERM domain containing protein 7 interacts with the Rho GDP dissociation inhibitor and specifically activates Rac1 signaling.PLoS One. 2013 Aug 13;8(8):e73108. doi: 10.1371/journal.pone.0073108. eCollection 2013. PLoS One. 2013. PMID: 23967341 Free PMC article.
FERM domain containing protein 7 (FRMD7) upregulates the expression of neuronal cytoskeletal proteins and promotes neurite outgrowth in Neuro-2a cells.Mol Vis. 2012;18:1428-35. Epub 2012 Jun 1. Mol Vis. 2012. PMID: 22690121 Free PMC article.
A novel interaction between FRMD7 and CASK: evidence for a causal role in idiopathic infantile nystagmus.Hum Mol Genet. 2013 May 15;22(10):2105-18. doi: 10.1093/hmg/ddt060. Epub 2013 Feb 12. Hum Mol Genet. 2013. PMID: 23406872 Free PMC article.
The role of the Rho GTPases in neuronal development.Genes Dev. 2005 Jan 1;19(1):1-49. doi: 10.1101/gad.1256405. Genes Dev. 2005. PMID: 15630019 Review.