Soto-Perez Jaseph, Baumgartner Marybeth, Kanadia Rahul N
Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT, United States.
Department of Genetics, Yale School of Medicine, New Haven, CT, United States.
Front Neurosci. 2020 Dec 18;14:617513. doi: 10.3389/fnins.2020.617513. eCollection 2020.
An expanded cortex is a hallmark of human neurodevelopment and endows increased cognitive capabilities. Recent work has shown that the cell cycle-related gene is essential for proper cortical development. Patients who have mutations in exhibit congenital microcephaly as a primary phenotype. At the cellular level, is essential for interkinetic nuclear migration and mitosis of radial glial cells, which translates to an indispensable role in neurodevelopment. The nuclear migration function of is well conserved across Opisthokonta. In mammals, multiple isoforms containing alternate terminal exons, which influence the functionality of , have been reported. It has been noted that the pattern of terminal exon usage mirrors patterns of cortical complexity in mammals. To provide context to these findings, here, we provide a comprehensive review of the literature regarding , its molecular biology and physiological relevance at the cellular and organismal levels. In particular, we outline the potential roles of in progenitor cell behavior and explore the spectrum of pathogenic variants. Moreover, we assessed the evolutionary conservation of and interrogated whether the usage of alternative terminal exons is characteristic of species with gyrencephalic cortices. We found that gyrencephalic species are more likely to express transcripts that use the human-associated terminal exon, whereas lissencephalic species tend to express transcripts that use the mouse-associated terminal exon. Among gyrencephalic species, the human-associated terminal exon was preferentially expressed by those with a high order of gyrification. These findings underscore phylogenetic relationships between the preferential usage of terminal exon and high-order gyrification, which provide insight into cortical evolution underlying high-order brain functions.
大脑皮层扩张是人类神经发育的一个标志，并赋予了增强的认知能力。最近的研究表明，细胞周期相关基因对于正常的皮层发育至关重要。在该基因中发生突变的患者表现出先天性小头畸形作为主要表型。在细胞水平上，该基因对于放射状胶质细胞的核内运动和有丝分裂至关重要，这在神经发育中转化为不可或缺的作用。该基因的核迁移功能在所有后鞭毛生物中都得到了很好的保守。在哺乳动物中，已经报道了含有交替末端外显子的多种异构体，这些异构体影响该基因的功能。值得注意的是，末端外显子的使用模式反映了哺乳动物皮层复杂性的模式。为了给这些发现提供背景信息，在此，我们对有关该基因及其在细胞和生物体水平上的分子生物学和生理相关性的文献进行了全面综述。特别是，我们概述了该基因在祖细胞行为中的潜在作用，并探索了该基因致病变体的范围。此外，我们评估了该基因的进化保守性，并询问了使用替代末端外显子是否是具有脑回状皮层的物种的特征。我们发现，具有脑回状皮层的物种更有可能表达使用与人类相关的末端外显子的转录本，而无脑回的物种倾向于表达使用与小鼠相关的末端外显子的转录本。在具有脑回状皮层的物种中，与人类相关的末端外显子优先被那些脑回化程度高的物种表达。这些发现强调了该基因末端外显子的优先使用与高阶脑回化之间的系统发育关系，这为高阶脑功能背后的皮层进化提供了见解。
