14-3-3 Proteins in Brain Development: Neurogenesis, Neuronal Migration and Neuromorphogenesis

Abstract

The 14-3-3 proteins are a family of highly conserved, multifunctional proteins that are highly expressed in the brain during development. Cumulatively, the seven 14-3-3 isoforms make up approximately 1% of total soluble brain protein. Over the last decade, evidence has accumulated implicating the importance of the 14-3-3 protein family in the development of the nervous system, in particular cortical development, and have more recently been recognized as key regulators in a number of neurodevelopmental processes. In this review we will discuss the known roles of each 14-3-3 isoform in the development of the cortex, their relation to human neurodevelopmental disorders, as well as the challenges and questions that are left to be answered. In particular, we focus on the 14-3-3 isoforms and their involvement in the three key stages of cortical development; neurogenesis and differentiation, neuronal migration and neuromorphogenesis and synaptogenesis.

Keywords: 14-3-3 proteins; neurite growth; neurite initiation; neurodevelopmental disorders; neurogenesis; neuromorphogenesis; neuronal migration; synaptogenesis.

Figure 1

Schematic illustration of some of the known functions of 14-3-3 proteins. (A) 14-3-3 proteins are able to bind phosphorylated targets and prevent their dephosphorylation by phosphatases. (B) 14-3-3 proteins can bind phosphorylated targets and block protein-protein or protein-DNA interaction sites. (C) 14-3-3 proteins are able to bind their targets and block localization signals, including nuclear localization signals, thus altering their targets subcellular localization. (D) 14-3-3 proteins can produce direct conformational changes on their targets by acting as rigid structures. (E) 14-3-3 proteins can act as rigid scaffolding structures and bind multiple targets to bring them into close proximity to one another. (F) 14-3-3 proteins can bind their target and block ubiquitination sites thus preventing the subsequent degradation of their target or they may bind their target and increase ubiquitination and subsequent degradation.

Figure 2

Illustration demonstrating the role of radial glial cells and intermediate progenitor cells (IPCs) in neurogenesis during cortical development. Three isoforms, 14-3-3ε, ζ and γ, are known to be expressed in these cells during cortical development. Further analysis is required for the remaining isoforms. VZ, Ventricular Zone; SVZ, Subventricular Zone.

Figure 3

Schematic model of the functions of 14-3-3ε and 14-3-3ζ in neurogenesis and neuronal differentiation during cortical development, reproduced with permission from the Society for Neuroscience (Toyo-Oka et al., 2014). (A) In wild-type (WT) progenitor cells, 14-3-3ε and ζ interact with δ-catenin and regulate its ubiquitination and subsequent degradation. δ-catenin then may regulate the stability of β-catenin and αN-catenin (dotted lines). The catenin proteins then activate the Rho family of GTPases, which in turn results in the phosphorylation of Limk1 through Pak and ROCK proteins. Then, phosphorylated Limk1 phosphorylates cofilin. Phosphorylated cofilin is inactive and will not sever F-actin, resulting in accelerated F-actin formation. (B) In contrast, when the progenitor cells are deficient in 14-3-3ε and ζ, the δ-catenin protein levels increase. This results in an opposite cascade of events resulting in increased neurogenesis and neuronal differentiation as well as defects in the subsequent neuronal migration.

Figure 4

Schematic illustration of neurite initiation. Illustration of the typical stages of neurite initiation. In stage 1, actin based lamellipodia type structures rapidly form and retract. In stage 2, microtubules begin to invade and stabilize lamellipodia structures preventing their collapse. In stage 3, neurites that have been invaded by microtubules become stable structures and begin to extend in stage 4. The overexpression of 14-3-3ε prevents the invasion of microtubules into forming neurites as seen in stage 2, thus disrupting neurite formation.

Figure 5

Schematic illustration of the regulation of neurite initiation by 14-3-3ε during cortical development. (A) Under normal conditions, 14-3-3ε binds to doublecortin (Dcx) at phosphorylated threonine-42 (P-T42). The remaining Dcx that is not bound to 14-3-3ε is rapidly ubiquitinated and subsequently degraded. Dcx stabilized by 14-3-3ε will then bind to microtubules, allowing for normal microtubule dynamics. During neurite initiation, microtubules are able to enter and stabilize lamellipodia allowing for normal neurite initiation. (B) When 14-3-3ε is overexpressed, there is increased binding of 14-3-3ε to Dcx, preventing its ubiquitination and subsequent degradation, resulting in an increase in Dcx protein levels. The increased Dcx binds to microtubules in excess, and this disrupts normal microtubule dynamics. This prevents microtubules from invading lamellipodia type structures during neurite initiation thus inhibiting normal neurite formation.