Human NDE1 splicing and mammalian brain development

Abstract

Exploring genetic and molecular differences between humans and other close species may be the key to explain the uniqueness of our brain and the selective pressures under which it evolves. Recent discoveries unveiled the involvement of Nuclear distribution factor E-homolog 1 (NDE1) in human cerebral cortical neurogenesis and suggested a role in brain evolution; however the evolutionary changes involved have not been investigated. NDE1 has a different gene structure in human and mouse resulting in the production of diverse splicing isoforms. In particular, mouse uses the terminal exon 8 T, while Human uses terminal exon 9, which is absent in rodents. Through chimeric minigenes splicing assay we investigated the unique elements regulating NDE1 terminal exon choice. We found that selection of the terminal exon is regulated in a cell dependent manner and relies on gain/loss of splicing regulatory sequences across the exons. Our results show how evolutionary changes in cis as well as trans acting signals have played a fundamental role in determining NDE1 species specific splicing isoforms supporting the notion that alternative splicing plays a central role in human genome evolution, and possibly human cognitive predominance.

Nde1 promotes diverse dynein functions through differential interactions and exhibits an isoform-specific proteasome association

“…Because of the diverse cellular roles of Nde1, testing the functional consequence of the Nde1-proteasome interaction will require Nde1 mutants that specifically disrupt the proteasome interaction without altering other Nde1 functions. To date, the C-terminal exons of Nde1 do not have other ascribed functions ( Mosca et al. , 2017 ).…”

“…In contrast, Nde1_SSSC is generally considered the canonical human isoform but is comparatively recently evolved ( Bradshaw et al. , 2009 ; Mosca et al. , 2017 ), having annotated homologues only in a few species of primates and dog.…”

The NDE1 genomic locus can affect treatment of psychiatric illness through gene expression changes related to microRNA-484

“…It is therefore very likely that any event which affects either the expression or alternate splicing of NDE1 would also impact upon miR-484 expression. That many of the SNPs of the NDE1 haplotypes are found in the 3′-most intron of NDE1 ( figure 2 ), which contains many motifs that regulate NDE1 splicing [ 61 ], therefore allows speculation that the SNPs could affect miR-484 expression indirectly through modulation of NDE1 splicing events.…”

TheNDE1genomic locus can affect treatment of psychiatric illness through gene expression changes related to MicroRNA-484

“…It is therefore very likely that any event which affects either the expression or alternate splicing of NDE1 would also impact upon miR-484 expression. That many of the SNPs of the NDE1 haplotypes are found in the 3 0 -most intron of NDE1 (figure 2), which contains many motifs that regulate NDE1 splicing [61], therefore allows speculation that the SNPs could affect miR-484 expression indirectly through modulation of NDE1 splicing events.…”