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Role of NDE1 in the Development and Evolution of the Gyrified Cortex

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.

SUBMITTER: Soto-Perez J

PROVIDER: S-EPMC7775536 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Project description:Differences in brain structure between species have long fascinated evolutionary biologists. Understanding how these differences arise requires knowing how they are generated in the embryo. Growing evidence in the field of evolutionary developmental biology (evo-devo) suggests that morphological differences between species result largely from changes in the spatiotemporal regulation of gene expression during development. Corresponding changes in functional cellular behaviors (morphogenetic mechanisms) are only beginning to be explored, however. Here we show that spatiotemporal patterns of tissue contractility are sufficient to explain differences in morphology of the early embryonic brain between disparate species. We found that enhancing cytoskeletal contraction in the embryonic chick brain with calyculin A alters the distribution of contractile proteins on the apical side of the neuroepithelium and changes relatively round cross-sections of the tubular brain into shapes resembling triangles, diamonds, and narrow slits. These perturbed shapes, as well as overall brain morphology, are remarkably similar to those of corresponding sections normally found in species such as zebrafish and Xenopus laevis (frog). Tissue staining revealed relatively strong concentration of F-actin at vertices of hyper-contracted cross-sections, and a finite element model shows that local contraction in these regions can convert circular sections into the observed shapes. Another model suggests that these variations in contractility depend on the initial geometry of the brain tube, as localized contraction may be needed to open the initially closed lumen in normal zebrafish and Xenopus brains, whereas this contractile machinery is not necessary in chick brains, which are already open when first created. We conclude that interspecies differences in cytoskeletal contraction may play a larger role in generating differences in morphology, and at much earlier developmental stages, in the brain than previously appreciated. This study is a step toward uncovering the underlying morphomechanical mechanisms that regulate how neural phenotypic differences arise between species.

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Role of NDE1 in the Development and Evolution of the Gyrified Cortex

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