Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome.
Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome.
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单基因神经发育障碍为疾病的发病机制提供了关键的见解，并帮助我们了解特定基因如何控制人类大脑的发育。Timothy综合征是由l型钙通道Cav1.2的错义突变引起的，与发育迟缓和自闭症有关。我们从蒂莫西综合征患者的诱导多能干细胞中生成皮层神经元前体细胞和神经元。来自这些个体的细胞在钙（Ca2+）信号和活性依赖基因表达方面存在缺陷。它们还表现出分化异常，包括在皮层下层和胼胝体投射神经元中表达的基因表达减少。此外，来自Timothy综合征个体的神经元显示酪氨酸羟化酶的异常表达和去甲肾上腺素和多巴胺的产生增加。这种表型可以通过罗斯科维汀治疗逆转，罗斯科维汀是一种细胞周期蛋白依赖性激酶抑制剂和非典型l型通道阻滞剂。这些发现为Cav1.2调控人类皮层神经元的分化提供了强有力的证据，并为Timothy综合征患者自闭症的病因提供了新的见解。
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 . 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 . 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.