Neocortical and cerebellar developmental abnormalities in conditions of selective elimination of peroxisomes from brain or from liver
Neocortical and cerebellar developmental abnormalities in conditions of selective elimination of peroxisomes from brain or from liver
复制标题
DOI：
10.1002/jnr.21097
复制
发表时间：
2007-01-01
影响因子：
4.2
通讯作者：
Baes, Myriam
中科院分区：
文献类型：
--
作者：
Krysko, Olga;Hulshagen, Leen;Baes, Myriam
大脑皮层和小脑形成缺陷是过氧化物酶体生物发生障碍Zellweger综合征和该疾病小鼠模型的突出特征。本研究的目的是通过分析组织选择性消除过氧化物酶体的小鼠来研究肝脏和大脑过氧化物酶体对神经发育的影响。为此，将Pex5-IoxP小鼠与白蛋白/甲胎蛋白（Alfp）-Cre和巢蛋白（内斯）-Cre小鼠交配。Nes-Pex5基因敲除小鼠大脑中过氧化物酶体的局部消除导致皮质神经元迁移和小脑叶和裂隙形成延迟。颗粒细胞从外部颗粒层的迁移被推迟，浦肯野细胞的极化和分支，导致在一个不太复杂的分支模式和一个较小的树突树在P21。Alfp-Pex5基因敲除小鼠受到不同的影响，尽管在胚胎发育过程中过氧化物酶体从肝脏中不完全消除，但在出生后大脑新皮层中的神经元迁移显示出部分停滞。在这些肝基因敲除小鼠的小脑形成中观察到主要异常，包括营养不良、叶状受损、颗粒细胞迁移延迟、细胞死亡增加和浦肯野细胞树枝化发育不良。总之，这些数据表明，从肝脏和大脑的过氧化物酶体功能的情况下损害皮质神经元的迁移和成熟的小脑，但不同的致病机制可能涉及。(c)2006 Wiley-Liss，Inc.
Defects in the formation of the cerebral cortex and the cerebellum are a prominent feature of the peroxisome biogenesis disorder Zellweger syndrome and in mouse models for this disease. The aim of the present study was to investigate the impact of liver and brain peroxisomes on neurodevelopment by analyzing mice with tissue-selective elimination of peroxisomes. To this end, Pex5-IoxP mice were bred with albumin/alpha-fetoprotein (Alfp)-Cre and nestin (Nes)-Cre mice. Local elimination of peroxisomes from the brain in Nes-Pex5 knockout mice caused a delay of cortical neuronal migration and of the formation of cerebellar folia and fissures. Migration of granule cells from the external granular layer was retarded, as was the polarization and branching of Purkinje cells, resulting in a less complex branching pattern and a smaller dendritic tree at P21. The Alfp-Pex5 knockout mice were affected differently, displaying a partial arrest of neuronal migration in the cerebral neopallium in the postnatal period despite of the incomplete elimination of peroxisomes from liver during embryonic development. Major abnormalities were seen in the formation of the cerebellum of these liver knockout mice, including hypotrophy, impaired foliation, a delay of granule cell migration, increased cell death, and stunted Purkinje cell arborization. In conclusion, these data demonstrate that absence of peroxisomal function both from liver and brain impairs cortical neuronal migration and maturation of the cerebellum, but different pathogenic mechanisms might be involved. (c) 2006 Wiley-Liss, Inc.