Progranulin modulates zebrafish motoneuron development in vivo and rescues truncation defects associated with knockdown of Survival motor neuron 1.
Progranulin modulates zebrafish motoneuron development in vivo and rescues truncation defects associated with knockdown of Survival motor neuron 1.
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DOI：
10.1186/1750-1326-5-41
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发表时间：
2010-10-14
影响因子：
15.1
通讯作者：
Bennett HP
中科院分区：
文献类型：
--
作者：
Chitramuthu BP;Baranowski DC;Kay DG;Bateman A;Bennett HP
颗粒蛋白前体（PGRN）是由GRN基因编码的一种分泌型糖蛋白生长因子，参与多种生理和病理生理过程。由GRN基因内的常染色体显性突变引起的PGRN单倍不足导致额颞叶变性（FTLD）形式的进行性神经元萎缩。这种形式的疾病与携带泛素化TAR DNA结合蛋白-43（TDP-43）分子标记（FTLD-U）的神经元包涵体相关。PGRN在体外的神经营养特性最近已被报道，但PGRN在神经元中的作用还没有得到很好的理解。在这里，我们记录的神经元的表达和功能的PGRN在脊髓运动神经元（MN）的成熟和分支在体内使用斑马鱼，脊椎动物胚胎发育的一个良好的模型。斑马鱼胚胎的整体原位杂交和免疫组织化学分析显示，zfPGRN-A在外周和中枢神经系统内表达，包括脊髓内的尾初级（CaP）MN。反义吗啉代寡核苷酸介导的zfPGRN-A mRNA翻译的敲低破坏了正常的CaP MN发育，导致截短的MN和不适当的早期分支。zfPGRN-A mRNA的异位过表达导致MN分支增加，并挽救了zfPGRN-A表达敲低所带来的截短缺陷。测试了PGRN与已建立的MN发育途径相互作用的能力。发现PGRN过表达逆转由运动神经元存活1（smn 1）敲低引起的截短缺陷。这涉及小核糖核蛋白生物合成RNA加工，其突变导致人类脊髓性肌萎缩症（SMA）。它没有逆转通过敲低NRP-1（一种脑信号蛋白辅助受体）的表达干扰神经元引导通路而引起的MN缺陷。MN内PGRN的表达和由mRNA敲低和过表达引起的观察到的表型与脊髓MN发育和分支的调节作用一致。这项研究首次在体内证明了PGRN的神经营养特性，并提出了未来可能在治疗神经退行性疾病中的治疗应用。
Progranulin (PGRN) encoded by the GRN gene, is a secreted glycoprotein growth factor that has been implicated in many physiological and pathophysiological processes. PGRN haploinsufficiency caused by autosomal dominant mutations within the GRN gene leads to progressive neuronal atrophy in the form of frontotemporal lobar degeneration (FTLD). This form of the disease is associated with neuronal inclusions that bear the ubiquitinated TAR DNA Binding Protein-43 (TDP-43) molecular signature (FTLD-U). The neurotrophic properties of PGRN in vitro have recently been reported but the role of PGRN in neurons is not well understood. Here we document the neuronal expression and functions of PGRN in spinal cord motoneuron (MN) maturation and branching in vivo using zebrafish, a well established model of vertebrate embryonic development. Whole-mount in situ hybridization and immunohistochemical analyses of zebrafish embryos revealed that zfPGRN-A is expressed within the peripheral and central nervous systems including the caudal primary (CaP) MNs within the spinal cord. Knockdown of zfPGRN-A mRNA translation mediated by antisense morpholino oligonucleotides disrupted normal CaP MN development resulting in both truncated MNs and inappropriate early branching. Ectopic over-expression of zfPGRN-A mRNA resulted in increased MN branching and rescued the truncation defects brought about by knockdown of zfPGRN-A expression. The ability of PGRN to interact with established MN developmental pathways was tested. PGRN over-expression was found to reverse the truncation defect resulting from knockdown of Survival of motor neuron 1 (smn1). This is involved in small ribonucleoprotein biogenesis RNA processing, mutations of which cause Spinal Muscular Atrophy (SMA) in humans. It did not reverse the MN defects caused by interfering with the neuronal guidance pathway by knockdown of expression of NRP-1, a semaphorin co-receptor. Expression of PGRN within MNs and the observed phenotypes resulting from mRNA knockdown and over-expression are consistent with a role in the regulation of spinal cord MN development and branching. This study presents the first in vivo demonstration of the neurotrophic properties of PGRN and suggests possible future therapeutic applications in the treatment of neurodegenerative diseases.
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影响因子：
64.8
作者：
Cruts, Marc;Gijselinck, Ilse;Van Broeckhoven, Christine
通讯作者：
Van Broeckhoven, Christine
影响因子：
82.9
作者：
He, ZH;Ong, CHP;Bateman, A
通讯作者：
Bateman, A
影响因子：
4
作者：
Bateman, Andrew;Bennett, Hugh P. J.
通讯作者：
Bennett, Hugh P. J.
影响因子：
2.5
作者：
Feldner, J;Becker, T;Becker, CG
通讯作者：
Becker, CG
影响因子：
5.3
作者：
Alias, Laura;Bernal, Sara;Tizzano, Eduardo F.
通讯作者：
Tizzano, Eduardo F.