Abstract
An expanded cortex is a hallmark of human neurodevelopment and endows increased cognitive capabilities. Recent work has shown that the cell cycle-related gene NDE1 is essential for proper cortical development. Patients who have mutations in NDE1 exhibit congenital microcephaly as a primary phenotype. At the cellular level, NDE1 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 NDE1 is well conserved across Opisthokonta. In mammals, multiple isoforms containing alternate terminal exons, which influence the functionality of NDE1, 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 NDE1, its molecular biology and physiological relevance at the cellular and organismal levels. In particular, we outline the potential roles of NDE1 in progenitor cell behavior and explore the spectrum of NDE1 pathogenic variants. Moreover, we assessed the evolutionary conservation of NDE1 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 NDE1 terminal exon and high-order gyrification, which provide insight into cortical evolution underlying high-order brain functions.
Highlights
In mammalian evolution, the brain has undergone significant change
We have explored the roles of Nde1 in progenitor cell behavior and mitosis, the genotype–phenotype relationships of NDE1 associated developmental disorders, and most importantly, we identified relationships between the pattern of NDE1 terminal exon usage and the development of highly gyrencephalic cortices
Experimental findings in mouse models and cell culture have provided insight into the functional mechanism of Nde1, these studies do not recapitulate the pathophysiology of NDE1 mutation-linked microcephaly in humans
Summary
The brain has undergone significant change. in the human lineage, the cerebral cortex has vastly expanded, which underlies our self-awareness, increased intellectual capacity, and other higher-order executive functions (Geschwind and Rakic, 2013). As part of the complex, NDE1 can interact with centromere protein F (CENP-F) at different subcellular localization to control nuclear migration, cell cycle progression, and mitosis (Vergnolle and Taylor, 2007; Bertipaglia et al, 2018; Doobin and Vallee, 2018). It has been proposed that NDE1mediated deciliation is the result of NDE1 sequestering LC8 at the basal body, which prevents retrograde dynein from contributing to the formation and maintenance of the primary cilium (Kim et al, 2011) This interaction may be a driving force in primary cilium resorption and the subsequent liberation of the captive centriole, regulating progenitor cell mitotic progression. Functional redundancy between NDE1 and NDEL1 allows both of these to form motor complexes with LIS1 and dynein, mediate nuclear migration, and interact with CENP-F (Vergnolle and Taylor, 2007; Doobin et al, 2016). Clinical evidence has shown that patients with NDE1 pathogenic variants do exhibit disorganized cortical layers (Bakircioglu et al, 2011)
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