Blocking Kallikrein 6 promotes developmental myelination.
Blocking Kallikrein 6 promotes developmental myelination.
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DOI：
10.1002/glia.24100
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发表时间：
2022-03
期刊：
影响因子：
6.2
通讯作者：
Scarisbrick IA
中科院分区：
文献类型：
--
作者：
Yoon H;Triplet EM;Simon WL;Choi CI;Kleppe LS;De Vita E;Miller AK;Scarisbrick IA
激肽释放酶相关肽酶6（Klk 6）是一种分泌型丝氨酸蛋白酶，在少突胶质细胞中高度表达，并与脱髓鞘条件有关。为了深入了解Klk 6对少突胶质细胞生物学的重要性，我们使用雄性和雌性小鼠的脊髓作为模型，研究了全局Klk 6基因敲除对CNS发育髓鞘形成的影响。结果表明，Klk 6表达的组成性缺失加速了少突胶质细胞的发育分化，包括髓鞘蛋白如MBP、PLP和CNCL 2的表达增加，CC-1+成熟少突胶质细胞的数量增加，以及出生后第一周结束时髓鞘厚度的增加。在脊髓中的7天Klk 6基因敲除还观察到的前髓鞘信号通路ERK和AKT，脂肪酸2-羟化酶的表达，和髓鞘调节转录因子的协同升高。脊髓脂质的LC/MS/MS定量显示鞘氨醇和鞘磷脂在髓鞘形成高峰时Klk 6敲除中升高。来源于Klk 6敲除的少突胶质细胞祖细胞（OPC）或用Klk 6抑制剂（DFKZ-251）处理的野生型OPC也显示出增加的MBP和PLP。此外，OPC培养物中Klk 6的抑制增强了脑源性神经营养因子驱动的分化。总之，这些发现表明，少突胶质细胞衍生的Klk 6可以作为自分泌或旁分泌变阻器，或制动器，对髓鞘形成前信号传导起作用，以调节发育和成人的髓鞘稳态。这些发现首次证明，在全球范围内，特别是在少突胶质细胞祖细胞中抑制Klk 6是增加中枢神经系统中少突胶质细胞分化和髓鞘产生早期阶段的策略。
Kallikrein related peptidase 6 (Klk6) is a secreted serine protease highly expressed in oligodendrocytes and implicated in demyelinating conditions. To gain insights into the significance of Klk6 to oligodendrocyte biology, we investigated the impact of global Klk6 gene knockout on CNS developmental myelination using the spinal cord of male and female mice as a model. Results demonstrate that constitutive loss of Klk6 expression accelerates oligodendrocyte differentiation developmentally, including increases in the expression of myelin proteins such as MBP, PLP and CNPase, in the number of CC-1+ mature oligodendrocytes, and myelin thickness by the end of the first postnatal week. Co-ordinate elevations in the pro-myelinating signaling pathways ERK and AKT, expression of fatty acid 2-hydroxylase, and myelin regulatory transcription factor were also observed in the spinal cord of 7d Klk6 knockouts. LC/MS/MS quantification of spinal cord lipids showed sphingosine and sphingomyelins to be elevated in Klk6 knockouts at the peak of myelination. Oligodendrocyte progenitor cells (OPCs)-derived from Klk6 knockouts, or wild type OPCs-treated with a Klk6 inhibitor (DFKZ-251), also showed increased MBP and PLP. Moreover, inhibition of Klk6 in OPC cultures enhanced brain derived neurotrophic factor-driven differentiation. Altogether, these findings suggest that oligodendrocyte-derived Klk6 may operate as an autocrine or paracrine rheostat, or brake, on pro-myelinating signaling serving to regulate myelin homeostasis developmentally and in the adult. These findings document for the first time that inhibition of Klk6 globally, or specifically in oligodendrocyte progenitors, is a strategy to increase early stages of oligodendrocyte differentiation and myelin production in the CNS.
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影响因子：
4.8
作者：
Angelo, PF;Lima, AR;Juliano, MA
通讯作者：
Juliano, MA
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