Neurabin-I Is Phosphorylated by Cdk5: Implications for Neuronal Morphogenesis and Cortical Migration

Abstract

The correct morphology and migration of neurons, which is essential for the normal development of the nervous system, is enabled by the regulation of their cytoskeletal elements. We reveal that Neurabin-I, a neuronal-specific F-actin-binding protein, has an essential function in the developing forebrain. We show that gain and loss of Neurabin-I expression affect neuronal morphology, neurite outgrowth, and radial migration of differentiating cortical and hippocampal neurons, suggesting that tight regulation of Neurabin-I function is required for normal forebrain development. Importantly, loss of Neurabin-I prevents pyramidal neurons from migrating into the cerebral cortex, indicating its essential role during early stages of corticogenesis. We demonstrate that in neurons Rac1 activation is affected by the expression levels of Neurabin-I. Furthermore, the Cdk5 kinase, a key regulator of neuronal migration and morphology, directly phosphorylates Neurabin-I and controls its association with F-actin. Mutation of the Cdk5 phosphorylation site reduces the phenotypic consequences of Neurabin-I overexpression both in vitro and in vivo, suggesting that Neurabin-I function depends, at least in part, on its phosphorylation status. Together our findings provide new insight into the signaling pathways responsible for controlled changes of the F-actin cytoskeleton that are required for normal development of the forebrain.

Cyclin-dependent Kinase 5 Regulates Endothelial Cell Migration and Angiogenesis

“…Thus, we propose that Cdk5 exerts its effects in endothelial cell migration via Rac1. This can be interpreted contrariwise to the report of Nikolic and colleagues (30), where neuronal Cdk5 has been elucidated as a downstream effector of Rac1. A different and much more interesting probable explanation might be a feedback loop between Cdk5 and Rac1.…”

“…Our findings are in line with reports concerning the function of Cdk5 in neurons. Neuronal Cdk5 affects the actin cytoskeleton by phosphorylating p27 kip and PAK1 as well as Neurabin-I (25,30,31); it controls dendritic spine morphology via phosphorylation of the RhoA guanine-nucleotide exchange factor (GEF) ephexin1 (32); and it phosphorylates the actin-binding proteins WAVE1 and WAVE2 (33,34).…”

New Perspectives on Genomic Imprinting, an Essential and Multifaceted Mode of Epigenetic Control in the Developing and Adult Brain

“…As discussed below, it is mediated by cellular processes that are influenced highly by genomic imprinting. Actin polymerization, which is critical for cell motility within the cortical plate, is promoted by CDKN1C and the maternally biased PPP1R9A (Causeret et al 2007, Tury et al 2012). Additionally, silencing of DCX by the maternally expressed miR134 inhibits cortical neuron migration (Gaughwin et al 2011).…”

What’s the hype about CDK5RAP2?

“…Some of the CDK5RAP2 effects on neuronal differentiation may be elicited via its interaction with CDK5R1 and indirectly CDK5, though it needs to be pointed out that binding of CDK5RAP2 to human CDK5R1 and regulation of CDK5 has not been seriously studied in human tissues. For CDK5, a pivotal role in neuronal differentiation, cell polarity and synaptic function has been reported [22,[66][67][68]. Moreover, the direct Cdk5rap2 interaction partner Cdk5r1 (p35) not only interacts with Cdk5, but also with Notch signaling pathway regulators [69].…”