title: Patient Mutations of the Intellectual Disability Gene KDM5C Downregulate Netrin G2 and Suppress Neurite Growth in Neuro2a Cells.
abstract: The X-linked lysine (K)-specific demethylase 5C (KDM5C) gene plays an important role in brain development and behavior. It encodes a histone demethylase that is involved in gene regulation in neuronal differentiation and morphogenesis. When mutated, it causes neuropsychiatric symptoms, such as intellectual disability, delayed language development, epilepsy, and impulsivity. To better understand how the patient mutations affect neuronal development, we expressed KDM5C mutants in Neuro2a cells, a mouse neuroblastoma cell line. Retinoic acid (RA)-induced neurite growth was suppressed by the mutation KDM5C (Y751C) , KDM5C (H514A) , and KDM5C (F642L) , but not KDM5C (D87G) or KDM5C (A388P) . RNA-seq analysis indicated an upregulation of genes important for neuronal development, such as Ntng2, Enah, Gas1, Slit2, and Dscam, in response to the RA treatment in control Neuro2a cells transfected with GFP or wild-type KDM5C. In contrast, in cells transfected with KDM5C (Y751C) , these genes were not upregulated by RA. Ntng2 was downregulated in cells with KDM5C mutations, concordant with the lower levels of H3K4 methylation at its promoter. Moreover, knocking down Ntng2 in control Neuro2a cells led to the phenotype of short neurites similar to that of cells with KDM5C (Y751C) , whereas Ntng2 overexpression in the mutant cells rescued the morphological phenotype. These findings provide new insight into the pathogenesis of phenotypes associated with KDM5C mutations.
authors.affiliation: Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, WA, USA.
authors.forename: Gengze
authors.initials: G
authors.lastname: Wei
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, USA.
authors.forename: Xinxian
authors.initials: X
authors.lastname: Deng
authors.affiliation: Department of Human Genetics, University of Michigan, 5815 Medical Science II, Ann Arbor, MI, USA.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Agarwal
authors.affiliation: Department of Human Genetics, University of Michigan, 5815 Medical Science II, Ann Arbor, MI, USA.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Iwase
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Disteche
authors.affiliation: Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, WA, USA. junxu@vetmed.wsu.edu.
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D015536:Down-Regulation; D005260:Female; D056466:Histone Demethylases; D006657:Histones / Q000378:metabolism; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D000075385:Netrins; D000071446:Neuronal Outgrowth; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics* / Q000378:metabolism; D011499:Protein Processing, Post-Translational
chemical_list: D006657:Histones; D009419:Nerve Tissue Proteins; D000075385:Netrins; C456263:Ntng2 protein, mouse; D056466:Histone Demethylases; C490173:Kdm5c protein, mouse; D010089:Oxidoreductases, N-Demethylating
keywords: Aggression; Autism; Memory; Sex difference; Synapse; X chromosome