Atypical neurogenesis in induced pluripotent stem cell (iPSC) from autistic individuals-猫眼课题宝

DOI：

10.1101/349415

发表时间：

2018-06

期刊：

bioRxiv

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

Dwaipayan Adhya;V. Swarup;R. Nagy;L. Dutan;C. Shum;K. Jozwik;M. Mendez;J. Horder;P. Nowosiad;Irene O. Lee;D. Skuse;E. Loth;D. Howley;F. Flinter;D. Murphy;G. McAlonan;D. Geschwind;J. Price;J. Carroll;D. Srivastava;S. Baron-Cohen

自闭症是一种异质性的疾病集合，具有复杂的分子基础。使用成年大脑进行的尸检研究的证据已经确定了可能发生在产前时期的基因的非典型共表达。最近使用从自闭症个体产生的诱导多能干细胞（iPSC）的研究表明，产前发育是与这种情况相关的病理生理学出现的关键时期。然而，这些差异在发育过程中出现的时间有多早，以及这种变化是否可以在多个大脑区域的发育过程中看到，目前尚不清楚。在这项研究中，我们调查了从典型发育个体和自闭症个体产生的iPSC之间的早期产前神经发育阶段是否不同。我们特别选择了具有异质性遗传背景且无已知合并症的彼此无关的自闭症个体，以探索常见的分子表型。iPSC向皮质谱系的分化揭示了从发育的早期阶段获得的异常细胞命运。有趣的是，异常分化发生在皮质分化过程中细胞增殖没有改变的情况下，不同于以往的研究。此外，这些效应似乎对皮质命运的获得具有特异性，因为iPSC向中脑谱系的分化并不伴随着典型发育和自闭症iPSC系之间的神经发生差异。对我们队列的一个子集进行的RNA测序进一步揭示了皮质分化过程中自闭症特异性特征，与尸检研究中观察到的相似，表明了一种潜在的共同生物学机制。总之，这些数据表明，与自闭症相关的独特发育差异可能在早期产前阶段建立。

Autism is a heterogenous collection of disorders with a complex molecular underpinning. Evidence from post mortem studies using adult brains have identified atypical co-expression of genes which may occur during the prenatal period. Recent studies using induced pluripotent stem cells (iPSCs) generated from autistic individuals have suggested that prenatal development is a critical period for the emergence of pathophysiology associated with this condition. However, how early during development these differences emerge and whether such alterations can be seen across the development of multiple brain regions is unclear. In this study we investigated whether early prenatal stages of neurodevelopment differ between iPSCs generated from typically developing and autistic individuals. We specifically selected autistic individuals unrelated to each other with a heterogeneous genetic background and no known comorbidities, to probe for common molecular phenotypes. Differentiation of iPSCs towards a cortical lineage revealed abnormal cell fate acquisition from an early stage of development. Interestingly, abnormal differentiation occurred in the absence of alteration in cell proliferation during cortical differentiation, differing from previous studies. Moreover, these effects appeared specific for the acquisition of a cortical fate, as differentiation of iPSCs towards a midbrain lineage was not accompanied by differences in neurogenesis between typically developing and autism iPSC lines. RNA-sequencing on a subset of our cohort further revealed autism-specific signatures during cortical differentiation similar to that observed in post mortem studies, indicating a potential common biological mechanism. Together, these data suggest unique developmental differences associated with autism may establish at an early prenatal stage.

Atypical neurogenesis in induced pluripotent stem cell (iPSC) from autistic individuals

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