Sonic Hedgehog Pathway Modulation Normalizes Expression of Olig2 in Rostrally Patterned NPCs With Trisomy 21.
Sonic Hedgehog Pathway Modulation Normalizes Expression of Olig2 in Rostrally Patterned NPCs With Trisomy 21.
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Sonic Hedgehog通路调控在具有21三体的鼻状核型鼻咽癌中低聚糖2的正常表达。
DOI：
10.3389/fncel.2021.794675
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发表时间：
2021
影响因子：
5.3
通讯作者：
Haydar TF
中科院分区：
文献类型：
--
作者：
Klein JA;Li Z;Rampam S;Cardini J;Ayoub A;Shaw P;Rachubinski AL;Espinosa JM;Zeldich E;Haydar TF
唐氏综合症患者的智力残疾与早期大脑发育的许多变化有关，包括神经祖细胞（npc）的增殖和分化以及大脑中髓磷脂的形成和维持。为了研究21三体对早期神经前体的影响，我们将来自唐氏综合征患者的两种等基因诱导多能干细胞分化为脑样和脊髓样npc，并通过激活Sonic hedgehog （SHH）通路促进其向少突胶质细胞的转变。在脊髓样三体细胞中，我们发现OLIG2或NKX2.2的表达没有差异，这两种转录因子对少突胶质细胞谱系的承诺至关重要。然而，在脑样三体npc中，OLIG2显著上调，并与NKX2.2的表达降低相关。我们发现，在分化过程中，SHH通路激动剂（SAG）的浓度增加可以使这种基因失调和鼻咽癌转移中的阻滞正常化。这些结果强调了唐氏综合征中基因表达的区域和细胞类型差异的重要性，并表明三体细胞中SHH信号的调节可以挽救神经谱系规范的早期紊乱步骤。
The intellectual disability found in people with Down syndrome is associated with numerous changes in early brain development, including the proliferation and differentiation of neural progenitor cells (NPCs) and the formation and maintenance of myelin in the brain. To study how early neural precursors are affected by trisomy 21, we differentiated two isogenic lines of induced pluripotent stem cells derived from people with Down syndrome into brain-like and spinal cord-like NPCs and promoted a transition towards oligodendroglial fate by activating the Sonic hedgehog (SHH) pathway. In the spinal cord-like trisomic cells, we found no difference in expression of OLIG2 or NKX2.2, two transcription factors essential for commitment to the oligodendrocyte lineage. However, in the brain-like trisomic NPCs, OLIG2 is significantly upregulated and is associated with reduced expression of NKX2.2. We found that this gene dysregulation and block in NPC transition can be normalized by increasing the concentration of a SHH pathway agonist (SAG) during differentiation. These results underscore the importance of regional and cell type differences in gene expression in Down syndrome and demonstrate that modulation of SHH signaling in trisomic cells can rescue an early perturbed step in neural lineage specification.
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影响因子：
11.8
作者：
Czerminski, Jan Tomasz;Lawrence, Jeanne Bentley
通讯作者：
Lawrence, Jeanne Bentley
影响因子：
3.7
作者：
Gonzales PK;Roberts CM;Fonte V;Jacobsen C;Stein GH;Link CD
通讯作者：
Link CD
DOI：
10.1016/j.cub.2015.07.056
发表时间：
2015-09-21
期刊：
Current biology : CB
影响因子：
--
作者：
Bechler ME;Byrne L;Ffrench-Constant C
通讯作者：
Ffrench-Constant C
影响因子：
6.2
作者：
Ghelman, Julia;Grewing, Laureen;Kuhlmann, Tanja
通讯作者：
Kuhlmann, Tanja
影响因子：
2.9
作者：
Bhattacharyya, Anita;McMillan, Erin;Svendsen, Clive N.
通讯作者：
Svendsen, Clive N.