Sulf1 and Sulf2 Differentially Modulate Heparan Sulfate Proteoglycan Sulfation during Postnatal Cerebellum Development: Evidence for Neuroprotective and Neurite Outgrowth Promoting Functions.
Sulf1 and Sulf2 Differentially Modulate Heparan Sulfate Proteoglycan Sulfation during Postnatal Cerebellum Development: Evidence for Neuroprotective and Neurite Outgrowth Promoting Functions.
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DOI：
10.1371/journal.pone.0139853
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Dierks T
中科院分区：
文献类型：
--
作者：
Kalus I;Rohn S;Puvirajesinghe TM;Guimond SE;Eyckerman-Kölln PJ;Ten Dam G;van Kuppevelt TH;Turnbull JE;Dierks T
Sulf 1和Sulf 2是细胞表面硫酸酯酶，其从硫酸乙酰肝素（HS）蛋白聚糖去除特异性6-O-硫酸酯基团，导致多种HS依赖性信号通路的调节。Sulf 1和Sulf 2基因敲除小鼠均表现出脑发育障碍和神经元突起生长缺陷。为了分析这些损伤背后的分子机制，我们专注于出生后小脑，其发育的主要特征是前体神经元的增殖，迁移和轴突生长过程。从Sulf 1或Sulf 2缺陷新生儿分离的原代小脑颗粒细胞的特征在于神经突长度和细胞存活减少。此外，Sulf 1缺乏导致迁移能力降低。观察到的细胞存活和神经突生长的损伤可能与Sulf特异性干扰信号传导途径相关，如FGF 2、GDNF和NGF所示。相比之下，Shh的信号，这决定了小脑皮层的层状组织，不受Sulf 1或Sulf 2基因敲除的影响。小脑HS的生化分析表明，在体内，第一次，6-O-，2-O-和N-硫酸化的敲除硫酸特异性的变化。在Sulf 2缺陷的小脑神经元表面发现了特定的HS表位的变化。该表位显示出有限的本地化到出生后小脑的外部颗粒层的内半部分，其中前体细胞经历最终成熟以形成突触接触。硫在出生后小脑的HS蛋白聚糖硫酸化模式中引入动态变化，从而协调大脑发育的基本机制。
Sulf1 and Sulf2 are cell surface sulfatases, which remove specific 6-O-sulfate groups from heparan sulfate (HS) proteoglycans, resulting in modulation of various HS-dependent signaling pathways. Both Sulf1 and Sulf2 knockout mice show impairments in brain development and neurite outgrowth deficits in neurons. To analyze the molecular mechanisms behind these impairments we focused on the postnatal cerebellum, whose development is mainly characterized by proliferation, migration, and neurite outgrowth processes of precursor neurons. Primary cerebellar granule cells isolated from Sulf1 or Sulf2 deficient newborns are characterized by a reduction in neurite length and cell survival. Furthermore, Sulf1 deficiency leads to a reduced migration capacity. The observed impairments in cell survival and neurite outgrowth could be correlated to Sulf-specific interference with signaling pathways, as shown for FGF2, GDNF and NGF. In contrast, signaling of Shh, which determines the laminar organization of the cerebellar cortex, was not influenced in either Sulf1 or Sulf2 knockouts. Biochemical analysis of cerebellar HS demonstrated, for the first time in vivo, Sulf-specific changes of 6-O-, 2-O- and N-sulfation in the knockouts. Changes of a particular HS epitope were found on the surface of Sulf2-deficient cerebellar neurons. This epitope showed a restricted localization to the inner half of the external granular layer of the postnatal cerebellum, where precursor cells undergo final maturation to form synaptic contacts. Sulfs introduce dynamic changes in HS proteoglycan sulfation patterns of the postnatal cerebellum, thereby orchestrating fundamental mechanisms underlying brain development.