The X-linked 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 mutations in Neuro2a cells, a mouse neuroblastoma
cell line. Retinoic acid (RA) induced-neurite growth was suppressed by the
mutation KDM5CY751C,
KDM5CH514A, and
KDM5CF642L, but not
KDM5CD87G or
KDM5CA388P. RNA-seq analysis indicated an
up-regulation 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
KDM5CY751C, these genes were not
up-regulated by RA. Ntng2 was down-regulated 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 KDM5CY751C, 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.