Novel Roles of Ndel1 in Cellular Development Mediated by Cytoskeleton Remodeling

Abstract

Some landmarks of neural development include the birth of neurons (neurogenesis), the migration of immature neurons (neuronal migration), outgrowth of axons and dendrites (neuronal differentiation), and the generation of synapse. Typically, these neurodevelopmental processes require morphological changes of neurons associated with motility or re-shaping, which is largely influenced by reorganization of cytoskeletons. Although many studies have suggested possible causes of neurodevelopmental diseases, there are still many unanswered questions and the complexity of the involvement of cytoskeleton in the pathogenesis of developmental disorders. In this context, identifying novel regulatory mechanisms of cytoskeleton-mediated signaling has great importance in understanding various physiological phenomena both in cellular/ neuronal developmental processes and related disorders. In this study, I identified novel roles of Nuclear distribution element-like 1 (Ndel1), which is a well-known susceptibility gene of schizophrenia, and two of its binding partners, Trio-associated repeats on actin (Tara), and Granule cell antiserum positive-14 (Gcap14), associated with major developmental processes mediated by cytoskeletal remodeling. Nuclear distribution element-like 1 (Ndel1) was firstly described as a regulator of the cytoskeleton in microtubule and it plays a role in diverse cellular processes like mitosis, neurogenesis, neurite outgrowth, and neuronal migration. Emerging evidence indicates that Ndel1 also serves as a docking platform for signaling proteins and modulates enzymatic activities (kinase, ATPase, oligopeptidase, and GTPase). Through its structural and signaling functions, Ndel1 is linked to the etiology of various mental illnesses and neurodevelopmental disorders. Trio-associated repeats on actin (Tara) was originally identified as an interactor with TRIO which is involved with neural tissue development. Tara is an actin-bundling protein and mutations of it are associated with human deafness DFNB28. In vitro, Tara forms dense F-actin bundles resembling the inner ear hair cell rootlet structure. Unlike Ndel1 or Tara, little is known about Granule cell antiserum positive-14 (Gcap14) except its putative relationship to the microtubule dynamics. Although both Tara and Gcap14 were identified as a functional regulator of actin and microtubule, most of their biological functions related to cellular or neuronal developmental processes remain elusive. In a yeast two-hybrid screen, I identified Tara and Gcap14 as new binding partners for Ndel1. Furthermore, through the interaction, they regulate Ndel1-mediated developmental processes including cell proliferation, migration, and neuronal differentiation. Also I found that both of Tara and Gcap14 alter Ndel1’s localization toward actin or microtubule structures while inducing Ndel1’s post-translational modification. Considering the massive involvement of Ndel1 in major developmental processes, identifying novel regulatory proteins which can affect Ndel1’s cellular functionalities can contribute to shed light into the causes of related developmental disorders.