Modelling and rescuing neurodevelopmental defect of Down syndrome using induced pluripotent stem cells from monozygotic twins discordant for trisomy 21.
Modelling and rescuing neurodevelopmental defect of Down syndrome using induced pluripotent stem cells from monozygotic twins discordant for trisomy 21.
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DOI：
10.1002/emmm.201302848
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发表时间：
2014-02
影响因子：
11.1
通讯作者：
Feki, Anis
中科院分区：
文献类型：
--
作者：
Hibaoui, Youssef;Grad, Iwona;Letourneau, Audrey;Sailani, M. Reza;Dahoun, Sophie;Santoni, Federico A.;Gimelli, Stefania;Guipponi, Michel;Pelte, Marie Francoise;Bena, Frederique;Antonarakis, Stylianos E.;Feki, Anis
唐氏综合征(21三体)是最常见的可存活的染色体疾病，伴有智力障碍和其他几种发育异常。在这里，我们报道了从与21三体不一致的同卵双胞胎中产生的诱导多能干细胞(IPSCs)的产生和鉴定，以消除基因组背景变异的影响。遗传分析在IPSC水平上观察到的变化和早期发育的第一近似值说明了唐氏综合症的发育疾病转录特征。此外，在NOD-SCID小鼠体内形成畸胎瘤时，我们观察到唐氏综合征IPSCs的神经分化异常，在体外，当分化为神经前体细胞和神经元时，我们观察到了异常的神经分化。这些缺陷与神经元、星形胶质细胞和少突胶质细胞的结构和密度的变化以及参与神经发生、谱系指定和分化的基因的错误表达有关。此外，我们提供了新的证据表明，21号染色体上的双特异性酪氨酸-(Y)-磷酸化调节的激酶1A(DYRK1A)可能与这些缺陷有关。重要的是，我们发现，在药理上或通过shRNA靶向DYRK1A导致了这些缺陷的相当大的纠正。
Down syndrome (trisomy 21) is the most common viable chromosomal disorder with intellectual impairment and several other developmental abnormalities. Here, we report the generation and characterization of induced pluripotent stem cells (iPSCs) derived from monozygotic twins discordant for trisomy 21 in order to eliminate the effects of the variability of genomic background. The alterations observed by genetic analysis at the iPSC level and at first approximation in early development illustrate the developmental disease transcriptional signature of Down syndrome. Moreover, we observed an abnormal neural differentiation of Down syndrome iPSCs in vivo when formed teratoma in NOD-SCID mice, and in vitro when differentiated into neuroprogenitors and neurons. These defects were associated with changes in the architecture and density of neurons, astroglial and oligodendroglial cells together with misexpression of genes involved in neurogenesis, lineage specification and differentiation. Furthermore, we provide novel evidence that dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A ( DYRK1A) on chromosome 21 likely contributes to these defects. Importantly, we found that targeting DYRK1A pharmacologically or by shRNA results in a considerable correction of these defects.
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影响因子：
3.5
作者：
Altafaj, X;Dierssen, M;Estivill, X
通讯作者：
Estivill, X
影响因子：
64.5
作者：
Ballas, N;Grunseich, C;Mandel, G
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Mandel, G
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5.3
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Haydar, Tarik F.
影响因子：
6.1
作者：
Ahn, Kyoung-Jin;Jeong, Hey Kyeong;Song, Woo-Joo
通讯作者：
Song, Woo-Joo
影响因子：
9.8
作者：
Canzonetta, Claudia;Mulligan, Claire;Nizetic, Dean
通讯作者：
Nizetic, Dean