14-3-3ε is important for neuronal migration by binding to NUDEL: a molecular explanation for Miller–Dieker syndrome

Abstract

Heterozygous deletions of 17p13.3 result in the human neuronal migration disorders isolated lissencephaly sequence (ILS) and the more severe Miller-Dieker syndrome (MDS). Mutations in PAFAH1B1 (the gene encoding LIS1) are responsible for ILS and contribute to MDS, but the genetic causes of the greater severity of MDS are unknown. Here, we show that the gene encoding 14-3-3epsilon (YWHAE), one of a family of ubiquitous phosphoserine/threonine-binding proteins, is always deleted in individuals with MDS. Mice deficient in Ywhae have defects in brain development and neuronal migration, similar to defects observed in mice heterozygous with respect to Pafah1b1. Mice heterozygous with respect to both genes have more severe migration defects than single heterozygotes. 14-3-3epsilon binds to CDK5/p35-phosphorylated NUDEL and this binding maintains NUDEL phosphorylation. Similar to LIS1, deficiency of 14-3-3epsilon results in mislocalization of NUDEL and LIS1, consistent with reduction of cytoplasmic dynein function. These results establish a crucial role for 14-3-3epsilon in neuronal development by sustaining the effects of CDK5 phosphorylation and provide a molecular explanation for the differences in severity of human neuronal migration defects with 17p13.3 deletions.

The DISC locus in psychiatric illness

“…185 14-3-3e thus complexes with LIS1 and NDEL1 in vivo and is responsible for maintaining their correct localization. Following their demonstration that DISC1 associates with 14-3-3e, Taya et al 88 demonstrated that many proteins were present in the DISC1 affinity column eluate in addition to KIF5B and 14-3-3e, including LIS1 and NDEL1.…”

The crystal structure of the non-liganded 14-3-3σ protein: insights into determinants of isoform specific ligand binding and dimerization

“…The specific elimination of certain 14-3-3 isoforms by genetic means or association of their deletion with distinct syndromes also supports the notion that isoform-specific functions and interactions exist. For example, deletion of 14-3-3ε is found in patients with Miller-Dieker Syndrome and results in a neuronal migration disorder [19]. In Drosophila melanogaster 14-3-3ε is required for correct timing of mitosis in undisturbed post-blastoderm cell cycles, whereas 14-3-3ζ is required for normal chromosomal segregation during syncytial mitosis [20].…”

Phosphoproteomic Analysis of the Developing Mouse Brain

“…This is of particular interest as loss of a single member of this family (14-3-3⑀) leads to abnormalities in neuronal migration during brain development in mice (4) and is tightly linked to the severity of lissencephalies resulting from genetic loss of Pafah1b1 (the gene encoding Lis1) in humans (4). A query of our dataset for phosphorylation sites creating these two modes of 14-3-3 binding identified 10 phosphopeptides (Fig.…”

“…The profound influence of protein phosphorylation on mammalian brain development has strong genetic support. This is exemplified by the important brain phenotypes observed in mice with loss of function mutations in genes encoding kinases such as p35/cyclin-dependent kinase 5 (Cdk5) 1 (1, 2), loss of tyrosine phosphorylation sites in signaling molecules such as the Reelin-stimulated adaptor protein Disabled-1 (3), or loss of genes encoding proteins that interact with phosphorylated protein motifs such as 14-3-3⑀ (4).…”