Departments of Pediatrics and Neurosurgery, Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine and Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, CA, USA.
Ann Neurol. 2012 Aug;72(2):224-33. doi: 10.1002/ana.23590. Epub 2012 Jul 17.
Chronic demyelination can result in axonopathy and is associated with human neurological conditions such as multiple sclerosis (MS) in adults and cerebral palsy in infants. In these disorders, myelin regeneration is inhibited by impaired differentiation of oligodendrocyte progenitors into myelin-producing oligodendrocytes. However, regulatory factors relevant in human myelin disorders and in myelin regeneration remain poorly understood. Here we have investigated the role of the transcription factor nuclear factor IA (NFIA) in oligodendrocyte progenitor differentiation during developmental and regenerative myelination.
NFIA expression patterns in human neonatal hypoxic-ischemic encephalopathy (HIE) and MS as well as developmental expression in mice were evaluated. Functional studies during remyelination were performed using a lysolecithin model, coupled with lentiviral misexpression of NFIA. The role of NFIA during oligodendrocyte lineage development was characterized using chick and mouse models and in vitro culture of oligodendrocyte progenitors. Biochemical mechanism of NFIA function was evaluated using chromatin immunoprecipitation and reporter assays.
NFIA is expressed in oligodendrocyte progenitors, but not differentiated oligodendrocytes during mouse embryonic development. Examination of NFIA expression in white matter lesions of human newborns with neonatal HIE, as well active MS lesions in adults, revealed that it is similarly expressed in oligodendrocyte progenitors and not oligodendrocytes. Functional studies indicate that NFIA is sufficient to suppress oligodendrocyte progenitor differentiation during adult remyelination and embryonic development through direct repression of myelin gene expression.
These studies suggest that NFIA participates in the control of oligodendrocyte progenitor differentiation and may contribute to the inhibition of remyelination in human myelin disorders.
慢性脱髓鞘可导致轴突变性，并与人类神经系统疾病有关，如成人多发性硬化症（MS）和婴儿脑瘫。在这些疾病中，少突胶质细胞前体细胞向髓鞘形成少突胶质细胞的分化受损，导致髓鞘再生受到抑制。然而，与人类髓鞘疾病和髓鞘再生相关的调节因子仍知之甚少。本研究旨在探讨转录因子核因子 IA（NFIA）在发育和再生髓鞘过程中少突胶质细胞前体细胞分化中的作用。
评估 NFIA 在人新生儿缺氧缺血性脑病（HIE）和 MS 中的表达模式以及在小鼠中的发育表达。使用溶卵磷脂模型进行再髓鞘化的功能研究，结合 NFIA 的慢病毒过表达。使用鸡和小鼠模型以及少突胶质细胞前体细胞体外培养，研究 NFIA 在少突胶质细胞谱系发育中的作用。通过染色质免疫沉淀和报告基因检测评估 NFIA 功能的生化机制。
NFIA 在小鼠胚胎发育过程中表达于少突胶质细胞前体细胞，但不表达于分化的少突胶质细胞。在新生儿 HIE 新生儿的白质病变以及成人活动期 MS 病变中检查 NFIA 的表达，发现其在少突胶质细胞前体细胞中表达相似，而不在少突胶质细胞中表达。功能研究表明，NFIA 通过直接抑制髓鞘基因的表达，足以在成年再髓鞘化和胚胎发育过程中抑制少突胶质细胞前体细胞的分化。
这些研究表明 NFIA 参与了少突胶质细胞前体细胞分化的控制，可能导致人类髓鞘疾病中髓鞘再生的抑制。
