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

2011; Nature Portfolio; Volume: 17; Issue: 12 Linguagem: Inglês

10.1038/nm.2576

1546-170X

Sergiu P. Paşca, Thomas Portmann, Irina Voineagu, Masayuki Yazawa, Aleksandr Shcheglovitov, Anca M. Paşca, Branden Cord, Theo D. Palmer, Sachiko Chikahisa, Seiji Nishino, Jonathan A. Bernstein, Joachim Hallmayer, Daniel H. Geschwind, Ricardo E. Dolmetsch,

Genomic variations and chromosomal abnormalities

Timothy syndrome is a neurodevelopmental disease that includes autism-like features. Using iPS-derived neurons from individuals with Timothy syndrome, Ricardo Dolmetsch and his colleagues identify changes in cortical neuron fate and neurotransmitter expression that may begin to explain the neural mechanisms that underlie this disorder. 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 autism1. 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 blocker2,3,4. 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.