Ablation of Vti1a/1b Triggers Neural Progenitor Pool Depletion and Cortical Layer 5 Malformation in Late-embryonic Mouse Cortex
Ablation of Vti1a/1b Triggers Neural Progenitor Pool Depletion and Cortical Layer 5 Malformation in Late-embryonic Mouse Cortex
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DOI：
10.1016/j.neuroscience.2021.03.021
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发表时间：
2021-03
期刊：
影响因子：
3.3
通讯作者：
G. Sokpor;Joachim Rosenbusch;A. Kunwar;M. Rickmann;Tran Tuoc;S. Rizzoli;V. Tarabykin;G. F. V. Mollard;K. Krieglstein;J. Staiger
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文献类型：
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作者：
G. Sokpor;Joachim Rosenbusch;A. Kunwar;M. Rickmann;Tran Tuoc;S. Rizzoli;V. Tarabykin;G. F. V. Mollard;K. Krieglstein;J. Staiger
皮质形态发生需要几个神经生物学事件，包括祖细胞的增殖和分化，成神经细胞的迁移，以及导致功能性神经回路的神经元成熟。这些神经发育过程受到许多因素的微妙调节。内体SNARE已经成为神经元生长的强大调节剂，除了它们在膜/囊泡运输中的众所周知的功能之外。然而，我们对它们对皮层形成的影响的理解是有限的。在这里，我们报告说，陷阱Vti 1a和Vti 1b（Vti 1a/1b）是正确的皮质发育的关键。在小鼠中Vti 1a/1b无效突变后，胚胎晚期突变皮质出现发育不良，并且其中的皮质祖细胞被耗尽超过正常。值得注意的是，皮质层5（L5）是明显的混乱，在Vti 1a/1b的情况下。后者的缺陷，加上Ctip 2表达L5神经元的明显凋亡，可能导致皮质脊髓和胼胝体的预测在Vti 1a/1b缺陷小鼠大脑的实质性损失。这些研究结果表明，Vti 1a/1b在皮质组织发生过程中发挥着关键的神经发育功能，当机制阐明时，可以清楚地了解内体SNARE如何调节大脑发育，或者它们的功能障碍如何影响神经系统疾病。
Cortical morphogenesis entails several neurobiological events, including proliferation and differentiation of progenitors, migration of neuroblasts, and neuronal maturation leading to functional neural circuitry. These neurodevelopmental processes are delicately regulated by many factors. Endosomal SNAREs have emerged as formidable modulators of neuronal growth, aside their well-known function in membrane/vesicular trafficking. However, our understanding of their influence on cortex formation is limited. Here, we report that the SNAREs Vti1a and Vti1b (Vti1a/1b) are critical for proper cortical development. Following null mutation of Vti1a/1b in mouse, the late-embryonic mutant cortex appeared dysgenic, and the cortical progenitors therein were depleted beyond normal. Notably, cortical layer 5 (L5) is distinctively disorganized in the absence of Vti1a/1b. The latter defect, coupled with an overt apoptosis of Ctip2-expressing L5 neurons, likely contributed to the substantial loss of corticospinal and callosal projections in the Vti1a/1b-deficient mouse brain. These findings suggest that Vti1a/1b serve key neurodevelopmental functions during cortical histogenesis, which when mechanistically elucidated, can lend clarity to how endosomal SNAREs regulate brain development, or how their dysfunction may have implications for neurological disorders.