State Key Laboratory of Cognitive Neuroscience and Learning, IDG/McGovern Institute for Brain Research, Beijing Normal University, New Cornerstone Science Laboratory, Beijing 100875, China; State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
Changping Laboratory, Beijing 102206, China.
Cell Rep. 2024 Aug 27;43(8):114508. doi: 10.1016/j.celrep.2024.114508. Epub 2024 Jul 16.
Lissencephaly is a rare brain malformation for which our understanding remains limited due to the absence of suitable animal models that accurately represent human phenotypes. Here, we establish doublecortin (DCX) knockout ferrets as a model that faithfully replicates key features of the disorder. We reveal the critical roles of DCX in neural progenitor cell proliferation and radial glial fiber extension, processes essential for normal cortical development. Utilizing single-nucleus RNA sequencing (snRNA-seq) and spatial transcriptomics, we provide a detailed atlas of the lissencephalic cortex, illustrating disrupted neuronal lamination and the specific interactions between inhibitory and excitatory neurons. These findings enhance our understanding of the cellular and molecular mechanisms underlying lissencephaly and highlight the potential of DCX knockout ferrets as a valuable tool for neurodevelopmental research, offering insights into both the pathology of lissencephaly and the general principles of brain development.
无脑回畸形是一种罕见的脑部畸形，由于缺乏准确反映人类表型的合适动物模型，我们对其的了解仍然有限。在这里，我们建立了双皮质素 (DCX) 敲除雪貂模型，该模型忠实地复制了该疾病的关键特征。我们揭示了 DCX 在神经祖细胞增殖和放射状胶质纤维延伸中的关键作用，这些过程对于正常皮质发育至关重要。利用单细胞 RNA 测序 (snRNA-seq) 和空间转录组学，我们提供了无脑回皮质的详细图谱，说明了神经元分层的破坏以及抑制性和兴奋性神经元之间的特定相互作用。这些发现增进了我们对无脑回畸形背后的细胞和分子机制的理解，并强调了 DCX 敲除雪貂作为神经发育研究有价值的工具的潜力，为无脑回畸形的病理学和大脑发育的一般原理提供了深入的了解。
