Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome

Abstract

Monogenic neurodevelopmental disorders provide key insights into the pathogenesis of disease and help us understand how specific genes control the development of the human brain. Timothy syndrome is caused by a missense mutation in the L-type calcium channel Cav1.2 that is associated with developmental delay and autism 1. We generated cortical neuronal precursor cells and neurons from induced pluripotent stem cells derived from individuals with Timothy syndrome. Cells from these individuals have defects in calcium (Ca2+) signaling and activity-dependent gene expression. They also show abnormalities in differentiation, including decreased expression of genes that are expressed in lower cortical layers and in callosal projection neurons. In addition, neurons derived from individuals with Timothy syndrome show abnormal expression of tyrosine hydroxylase and increased production of norepinephrine and dopamine. This phenotype can be reversed by treatment with roscovitine, a cyclin-dependent kinase inhibitor and atypical L-type–channel blocker 2, 3, 4. These findings provide strong evidence that Cav1.2 regulates the differentiation of cortical neurons in humans and offer new insights into the causes of autism in individuals with Timothy syndrome.

Modeling Williams syndrome with induced pluripotent stem cells

“…23,25,29,30 Although the findings of the differences in the number of dendritic segments, branching points and trees did not agree between the iPSC model and postmortem tissue, we did observed a similar trend for WS iPSC-derived neurons to have a higher number of dendritic segments and branching points, as observed in WS postmortem brains. It is possible that iPSC-derived neurons lack the dynamics from environmental inputs, and deficiencies in dendritic segments and branching points may occur later in development, resulting in the only partial dendritic changes observed in postmortem specimens.…”

A network of genetic repression and derepression specifies projection fates in the developing neocortex

“…Autistic patients seem to have callosal abnormalities (19)(20)(21)(22)(23)(24)(25)(26), and in this context it is relevant that Auts2, a gene associated with autism, is regulated by Tbr1, which in turn is regulated by Satb2, a callosal fate specification gene. Recent studies suggest that a mutation in CAv1/2 (an L-type calcium channel) that is associated with Timothy syndrome, a form of autism, results in lower numbers of Satb2-expressing cells and an increase in Ctip2-expressing cells (31). The authors suggest that the reduction in callosal neurons in Timothy syndrome is consistent with the emerging view that autism spectrum disorders arise from defects in connectivity between cortical areas (31).…”

“…Recent studies suggest that a mutation in CAv1/2 (an L-type calcium channel) that is associated with Timothy syndrome, a form of autism, results in lower numbers of Satb2-expressing cells and an increase in Ctip2-expressing cells (31). The authors suggest that the reduction in callosal neurons in Timothy syndrome is consistent with the emerging view that autism spectrum disorders arise from defects in connectivity between cortical areas (31).…”

Discovery of Rare Mutations in Autism: Elucidating Neurodevelopmental Mechanisms

“…For example, iPSC-derived neurons were generated from patients diagnosed with the autism-associated disorder TS, which results from mutations in the L-type calcium channel Ca v 1.2 and leads to decreased channel inactivation. TS neurons show dysregulation of genes involved in catecholamine synthesis, which can be reversed by treatment with an L-type-channel blocker, roscovitine [195]. In another study, disruption of calcium signaling, changes in gene expression, and decreased neurite growth were observed in iPSC-derived neurons from a nonsyndromic patient with autism with a translocation disrupting the cation channel gene TRPC6.…”