Normal Neurogenesis but abnormal gene expression in human Fragile X cortical progenitor cells
Normal Neurogenesis but abnormal gene expression in human Fragile X cortical progenitor cells
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DOI：
10.1089/scd.2007.0073
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发表时间：
2008-02-01
影响因子：
4
通讯作者：
Svendsen, Clive N.
中科院分区：
文献类型：
--
作者：
Bhattacharyya, Anita;McMillan, Erin;Svendsen, Clive N.
人类干细胞和祖细胞提供了一种研究发育早期事件的创新方法。对于这些细胞来说，一个令人兴奋的新机会是它们用于研究遗传疾病的潜在发育后果。因为许多疾病，从白血病到发育障碍，都是由单基因缺陷引起的，携带致病基因突变的干细胞和祖细胞在理解和治疗疾病方面是非常宝贵的。我们已经表征了携带导致神经发育障碍的单基因缺陷的人神经祖细胞（hNPC）。脆性X综合征（FX）FMR1基因的功能缺失突变导致神经发育的微妙变化和随后的FX特征性精神障碍。从携带FMR 1突变的胎儿皮质分离hNPC，以确定其增殖和分化中是否发生畸变。正如预期的那样，FX hNPC具有FMR 1基因产物脆性X智力低下蛋白（FMRP）的表达降低，并且这种降低在培养物和分化后得以维持。与先前发表的报告相反，FX hNPC的增殖及其分化为神经元与未受影响的对照没有不同。虽然FX hNPC的早期发育基本正常，但微阵列分析揭示了FX hNPC中信号转导基因表达的新变化。因此，hNPC具有内在的特征，可以研究这些特征以进一步我们对发育障碍如FX的理解和潜在治疗。
Human stem and progenitor cells offer an innovative way to study early events in development. An exciting new opportunity for these cells is their application to study the underlying developmental consequences of genetic diseases. Because many diseases, ranging from leukemias to developmental disorders, are caused by single-gene defects, stem and progenitor cells that carry disease-causing genetic mutations are invaluable in understanding and treating disease. We have characterized human neural progenitor (hNPCs) cells that carry a single-gene defect that leads to the neurodevelopmental. disorder Fragile X syndrome (FX). A loss-of-function mutation in the FMR1 gene leads to subtle changes in neural development and subsequent mental impairment characteristic of FX. hNPCs were isolated from fetal cortex carrying the FMR1 mutation to determine whether aberrations occur in their proliferation and differentiation. As expected, FX hNPCs have reduced expression of the FMR1 gene product Fragile X mental retardation protein (FMRP), and this decrease is maintained in culture and following differentiation. In contrast to a previously published report, the proliferation of FX hNPCs and their differentiation into neurons is not different from unaffected controls. Although the early development of FX hNPCs is essentially normal, microarray analysis reveals novel changes in the expression of signal transduction genes in FX hNPCs. Therefore, hNPCs have intrinsic characteristics that can be investigated to further our understanding and potential treatment of developmental disorders such as FX.