Abstract:
Neurons are post-mitotic cells, with microtubules playing crucial roles in axonal transport and growth. Kinesin family member 2c (KIF2C), a member of the Kinesin-13 family, possesses the ability to depolymerize microtubules and is involved in remodelling the microtubule lattice. Myocyte enhancer factor 2c (MEF2C) was initially identified as a regulator of muscle differentiation but has recently been associated with neurological abnormalities such as severe cognitive impairment, stereotyping, epilepsy and brain malformations when mutated or deleted. However, further investigation is required to determine which target genes MEF2C acts upon to influence neuronal function as a transcription regulator. Our data demonstrate that knockdown of both Mef2c and Kif2c significantly impacts spinal motor neuron development and behaviour in zebrafish. Luciferase reporter assays and chromosome immunoprecipitation assays, along with down/upregulated expression analysis, revealed that MFE2C functions as a novel transcription regulator for the Kif2c gene. Additionally, the knockdown of either Mef2c or Kif2c expression in E18 cortical neurons substantially reduces the number of primary neurites and axonal branches during neuronal development in vitro without affecting neurite length. Finally, depletion of Kif2c eliminated the effects of overexpression of Mef2c on the neurite branching. Based on these findings, we provided novel evidence demonstrating that MEF2C regulates the transcription of the Kif2c gene thereby influencing the axonal branching.
摘要:
神经元是有丝分裂后的细胞,微管在轴突运输和生长中起关键作用。Kinesin家族成员2c(KIF2C),Kinesin-13家族的一员,具有使微管解聚的能力,并参与了微管晶格的重塑。肌细胞增强因子2c(MEF2C)最初被确定为肌肉分化的调节因子,但最近与神经系统异常有关,例如严重的认知障碍。刻板印象,癫痫和大脑畸形时突变或删除。然而,需要进一步研究以确定MEF2C作用于哪些靶基因作为转录调节因子影响神经元功能.我们的数据表明,在斑马鱼中,Mef2c和Kif2c的敲减均显着影响脊髓运动神经元的发育和行为。荧光素酶报告基因测定和染色体免疫沉淀测定,随着下调/上调表达分析,揭示了MFE2C作为Kif2c基因的新型转录调节因子的功能。此外,E18皮质神经元中Mef2c或Kif2c表达的敲除大大减少了体外神经元发育过程中原代神经突和轴突分支的数量,而不影响神经突长度。最后,Kif2c的消耗消除了Mef2c过表达对神经突分支的影响。基于这些发现,我们提供了新的证据,证明MEF2C调节Kif2c基因的转录,从而影响轴突分支。