Partoens Michèle, De Meulemeester Ann-Sofie, Giong Hoi-Khoanh, Pham Duc-Hung, Lee Jeong-Soo, de Witte Peter A, Siekierska Aleksandra
Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, Belgium.
Disease Target Structure Research Centre, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea.
eNeuro. 2021 Sep 7;8(5). doi: 10.1523/ENEURO.0055-21.2021. Print 2021 Sep-Oct.
In recent years there has been extensive research on malformations of cortical development (MCDs) that result in clinical features like developmental delay, intellectual disability, and drug-resistant epilepsy (DRE). Various studies highlighted the contribution of microtubule-associated genes (including tubulin and kinesin encoding genes) in MCD development. It has been reported that mutations in , a member of the family, are linked to brain malformations and DRE. Although it is known that KIF2A functions by regulating microtubule depolymerization via an ATP-driven process, implications of loss of function remain partly unclear. Here, we present a novel knock-out zebrafish model, showing hypoactivity, habituation deficits, pentylenetetrazole-induced seizure susceptibility and microcephaly, as well as neuronal cell proliferation defects and increased apoptosis. Interestingly, larvae survived until adulthood and were fertile. Notably, our zebrafish knock-out model demonstrated many phenotypic similarities to mouse models. This study provides valuable insights into the functional importance of in zebrafish and phenotypical hallmarks related to mutations. Ultimately, this model could be used in a future search for more effective therapies that alleviate the clinical symptoms typically associated with MCDs.
近年来，针对导致发育迟缓、智力残疾和耐药性癫痫（DRE）等临床特征的皮质发育畸形（MCDs）开展了广泛研究。各项研究强调了微管相关基因（包括微管蛋白和驱动蛋白编码基因）在MCD发育中的作用。据报道， 家族成员 中的突变与脑畸形和DRE有关。尽管已知KIF2A通过ATP驱动的过程调节微管解聚发挥作用，但其功能丧失的影响仍部分不明。在此，我们展示了一种新型的 基因敲除斑马鱼模型，该模型表现出活动减少、习惯化缺陷、戊四氮诱导的癫痫易感性和小头畸形，以及神经元细胞增殖缺陷和细胞凋亡增加。有趣的是， 幼虫存活至成年且可育。值得注意的是，我们的 斑马鱼敲除模型与 小鼠模型表现出许多表型相似性。本研究为 基因在斑马鱼中的功能重要性以及与 突变相关的表型特征提供了有价值的见解。最终，该模型可用于未来寻找更有效疗法以缓解通常与MCDs相关的临床症状的研究。
