Abstract：
Dynein heavy chain (DYNC1H1) mutations can either lead to severe cerebral cortical malformations, or alternatively may be associated with the development of spinal muscular atrophy with lower extremity predominance (SMA-LED). To assess the origin of such differences, we studied a new Dync1h1 knock-in mouse carrying the cortical malformation p.Lys3334Asn mutation. Comparing with an existing neurodegenerative Dync1h1 mutant (Legs at odd angles, Loa, p.Phe580Tyr/+), we assessed Dync1h1\'s roles in cortical progenitor and especially radial glia functions during embryogenesis, and assessed neuronal differentiation. p.Lys3334Asn /+ mice exhibit reduced brain and body size. Embryonic brains show increased and disorganized radial glia: interkinetic nuclear migration occurs in mutants, however there are increased basally positioned cells and abventricular mitoses. The ventricular boundary is disorganized potentially contributing to progenitor mislocalization and death. Morphologies of mitochondria and Golgi apparatus are perturbed in vitro, with different effects also in Loa mice. Perturbations of neuronal migration and layering are also observed in p.Lys3334Asn /+ mutants. Overall, we identify specific developmental effects due to a severe cortical malformation mutation in Dync1h1, highlighting the differences with a mutation known instead to primarily affect motor function.
摘要：
Dynein重链（DYNC1H1）突变可导致严重的大脑皮质畸形，或者可能与下肢占优势的脊髓性肌萎缩症（SMA-LED）的发展有关。为了评估这种差异的起源，我们研究了一种携带皮质畸形p.Lys3334Asn突变的新型Dync1h1敲入小鼠。与现有的神经退行性Dync1h1突变体(腿在奇数角度，Loa,+/pPhe580Tyr),我们评估了Dync1h1在皮质祖细胞中的作用，尤其是在胚胎发生过程中的放射状神经胶质功能，并评估神经元分化。p.Lys3334Asn/+小鼠表现出减小的脑和体型。胚胎大脑显示出增加和杂乱无章的放射状神经胶质：在突变体中发生动力间核迁移，然而，有增加的基础定位细胞和无室有丝分裂。心室边界杂乱无章，可能导致祖细胞定位错误和死亡。线粒体和高尔基体的形态在体外受到干扰，在Loa小鼠中也有不同的效果。在p.Lys3334Asn/+突变体中也观察到神经元迁移和分层的扰动。总的来说,我们确定了由于Dync1h1中严重的皮质畸形突变引起的特定发育效应,并强调了与已知主要影响运动功能的突变的差异.
