Abstract
SummaryNeuronal polarity in the developing cortex begins during the early stages of neural progenitor migration toward the cortical plate and culminates with the specification of the axon and dendrites. Here, we demonstrate that the Ran-dependent nucleocytoplasmic transport machinery is essential for the establishment of cortical neuron polarity. We found that Ran-binding protein 1 (RanBP1) regulates axon specification and dendritic arborization in cultured neurons in vitro and radial neural migration in vivo. During axonogenesis, RanBP1 regulates the cytoplasmic levels of the polarity protein LKB1/Par4, and this is dependent on the nuclear export machinery. Our results show that downstream of RanBP1, LKB1 function is mediated by the STK25-GM130 pathway, which promotes axonogenesis through Golgi regulation. Our results indicate that the nucleocytoplasmic transport machinery is a main regulator of neuron polarity, including radial migration, and that the regulated export of LKB1 through RanBP1 is a limiting step of axonogenesis.
Highlights
Neuron polarity underpins neural circuit formation and function
Localization of Ran, RCC1, RanGAP, and Ran-binding protein 1 (RanBP1) in Mammalian Cortical Neurons we investigated whether regulated Ran-dependent nucleocytoplasmic transport promotes axon growth in vertebrate neurons using neonatal rat cortical neurons
Further supporting the hypothesis that RanBP1 plays a key role in regulating the availability of LKB1 during neuron polarity, we found that overexpression of LKB1 and STRADa did not generate additional axons when RanBP1 expression was decreased, and in 20% of the cases, no axon could be detected (Figures 3E–3G)
Summary
Neuron polarity underpins neural circuit formation and function. During cortex development, neuron polarity arises as the neuroepithelial progenitors exit the cell cycle and migrate radially from the ventricular zone toward the cortical plate. Radial migration is initiated by the polarized distribution of N-cadherin, which concentrates at one pole of newly differentiating neurons and defines the position of the first of two opposite neurites (Calderon de Anda et al, 2008; Gartner et al, 2012; Hatanaka and Murakami, 2002; Pollarolo et al, 2011). This early polarity event influences the latter specification of the axon and dendrites (Noctor et al, 2004). Whether regulated nuclear export of LKB1 is a regulatory step of neuron polarity has not been examined
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