Abnormal cerebellar development and Purkinje cell defects in Lgl1-Pax2 conditional knockout mice
Abnormal cerebellar development and Purkinje cell defects in Lgl1-Pax2 conditional knockout mice
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Lgl1-Pax2 条件敲除小鼠小脑发育异常和浦肯野细胞缺陷
DOI：
10.1016/j.ydbio.2014.07.007
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发表时间：
2014-11-01
影响因子：
2.7
通讯作者：
Gao, Jiangang
中科院分区：
文献类型：
--
作者：
Hou, Congzhe;Ding, Lingcui;Gao, Jiangang
LGL1最初被鉴定为果蝇中的肿瘤抑制因子，并被描述为上皮极性和不对称细胞分裂的关键调节因子。先前的一项研究表明，更多Cre介导的Lgl1基因敲除小鼠表现出显著的脑发育不良，并在出生后24小时内死亡。为了克服早期新生儿死亡，我们建立了由Pax2-Cre介导的Lgl1条件性基因敲除小鼠，Pax2-Cre在小脑几乎所有细胞中都有表达，我们检测了Lgl1在小脑中的功能。在突变小鼠中检测到运动协调性受损。与这种异常行为相一致的是，纯合子小鼠的小脑较小，叶较少，颗粒前体细胞(GPC)增殖减少，浦肯野细胞(PC)数量减少，树突状细胞发育不良。小脑中Lgl1的缺失导致脑室区神经前体细胞过度增殖和分化障碍。基于TUNEL检测，我们观察到突变小鼠小脑中的细胞凋亡增加。我们认为，分化受损和细胞凋亡增加可能是PC数量减少的原因之一。为了阐明Lgl1对小脑颗粒细胞的作用，我们用Math1-Cre特异性地删除了颗粒细胞中的Lgl1。有趣的是，Lgl1-Math1条件性基因敲除小鼠表现出正常的GPC增殖和小脑发育。因此，我们推测在Lgl1-Pax2条件性基因敲除小鼠中，GPC增殖的减少可能次要于PC数量的减少，PC分泌有丝分裂因子Sonic Hedgehog来调节GPC的增殖。综上所述，这些发现表明，Lgl1通过调节PC的发育，在小脑发育和叶状细胞的形成中发挥关键作用。(C)2014年，爱思唯尔公司出版。
Lgl1 was initially identified as a tumour suppressor in flies and is characterised as a key regulator of epithelial polarity and asymmetric cell division. A previous study indicated that More-Cre-mediated Lgl1 knockout mice exhibited significant brain dysplasia and died within 24 h after birth. To overcome early neonatal lethality, we generated Lgl1 conditional knockout mice mediated by Pax2-Cre, which is expressed in almost all cells in the cerebellum, and we examined the functions of Lgl1 in the cerebellum. Impaired motor coordination was detected in the mutant mice. Consistent with this abnormal behaviour, homozygous mice possessed a smaller cerebellum with fewer lobes, reduced granule precursor cell (GPC) proliferation, decreased Purkinje cell (PC) quantity and dendritic dysplasia. Loss of Lgl1 in the cerebellum led to hyperproliferation and impaired differentiation of neural progenitors in ventricular zone. Based on the TUNEL assay, we observed increased apoptosis in the cerebellum of mutant mice. We proposed that impaired differentiation and increased apoptosis may contribute to decreased PC quantity. To clarify the effect of Lgl1 on cerebellar granule cells, we used Math1-Cre to specifically delete Lgl1 in granule cells. Interestingly, the Lgl1-Math1 conditional knockout mice exhibited normal proliferation of GPCs and cerebellar development. Thus, we speculated that the reduction in the proliferation of GPCs in Lgl1-Pax2 conditional knockout mice may be secondary to the decreased number of PCs, which secrete the mitogenic factor Sonic hedgehog to regulate GPC proliferation. Taken together, these findings suggest that Lgl1 plays a key role in cerebellar development and folia formation by regulating the development of PCs. (C) 2014 Published by Elsevier Inc.