Prox1 Inhibits Proliferation and Is Required for Differentiation of the Oligodendrocyte Cell Lineage in the Mouse.
Prox1 Inhibits Proliferation and Is Required for Differentiation of the Oligodendrocyte Cell Lineage in the Mouse.
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DOI：
10.1371/journal.pone.0145334
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Hidalgo A
中科院分区：
文献类型：
--
作者：
Kato K;Konno D;Berry M;Matsuzaki F;Logan A;Hidalgo A
中枢神经系统损伤诱导成鞘神经胶质细胞的再生反应，包括细胞增殖，自发轴突髓鞘再生和有限的功能恢复，但分子机制尚未完全了解。在果蝇中，这涉及到控制神经胶质增殖和分化之间平衡的基因Notcho和Notch，操纵它们在神经胶质中的水平可以将对损伤的反应从预防转变为促进修复。在小鼠中，Notch 1维持NG 2少突胶质祖细胞（OPCs）处于祖细胞状态，但什么因子可能使少突胶质细胞（OL）分化和功能性髓鞘再生尚不清楚。在这里，我们问是否哺乳动物的同源物Prox 1，参与。我们的数据表明，Prox 1分布在NG 2 + OPCs和OLs的原代培养细胞，并在体内的小鼠脊髓。在原代OPCs中的SiRNA干扰抑制增加了细胞增殖，增加了NG 2 + OPC细胞数量，并减少了CC 1 + OL数量。在小鼠OL细胞谱系中的Prox 1条件性敲除增加了NG 2 + OPC细胞数量，并减少了CC 1 + OL数量。与对照组相比，溶血卵磷脂诱导的脱髓鞘损伤导致纯合Prox 1-/-条件性基因敲除小鼠中CC 1 + OL减少。值得注意的是，Prox 1-/-条件性基因敲除小鼠的病变比对照组小。总之，这些数据表明，Prox 1是抑制OPC增殖和OL分化所必需的，并且可能是再生胶质反应的相关组分。神经胶质细胞和干细胞在中枢神经系统损伤后促进再生和修复的治疗用途将受益于操纵Prox 1。
Central nervous system injury induces a regenerative response in ensheathing glial cells comprising cell proliferation, spontaneous axonal remyelination, and limited functional recovery, but the molecular mechanisms are not fully understood. In Drosophila, this involves the genes prospero and Notch controlling the balance between glial proliferation and differentiation, and manipulating their levels in glia can switch the response to injury from prevention to promotion of repair. In the mouse, Notch1 maintains NG2 oligodendrocyte progenitor cells (OPCs) in a progenitor state, but what factor may enable oligodendrocyte (OL) differentiation and functional remyelination is not understood. Here, we asked whether the mammalian homologue of prospero, Prox1, is involved. Our data show that Prox1 is distributed in NG2+ OPCs and in OLs in primary cultured cells, and in the mouse spinal cord in vivo. siRNA prox1 knockdown in primary OPCs increased cell proliferation, increased NG2+ OPC cell number and decreased CC1+ OL number. Prox1 conditional knockout in the OL cell lineage in mice increased NG2+ OPC cell number, and decreased CC1+ OL number. Lysolecithin-induced demyelination injury caused a reduction in CC1+ OLs in homozygous Prox1-/- conditional knockout mice compared to controls. Remarkably, Prox1-/- conditional knockout mice had smaller lesions than controls. Altogether, these data show that Prox1 is required to inhibit OPC proliferation and for OL differentiation, and could be a relevant component of the regenerative glial response. Therapeutic uses of glia and stem cells to promote regeneration and repair after central nervous system injury would benefit from manipulating Prox1.