DCXs Phosphorylation by Not Just aNother Kinase (JNK)

Abstract

The mammalian cortex is generally subdivided into six organized layers, which are formed during development in an organized fashion. This organized cortical layering is disrupted in case of mutations in the doublecortin (DCX) gene. DCX is a Microtubule Associated Protein (MAP). However, besides stabilization of microtubules, it may be involved in additional functions. The participation of this molecule in signal transduction is beginning to emerge via discovery of interacting molecules and its regulation by phosphorylation using several different kinases. We raise the hypothesis, that the combinatorial phosphorylation of DCX by different kinases and at different sites may be a molecular regulatory switch in the transition of a migrating neuron through multiple phases of migration. Our recent research has suggested the involvement of DCX in the JNK (Jun-N-terminal Kinase) pathway. The JNK pathway is linked to the reelin pathway, known to regulate cortical layering. Positioning of DCX in this signaling pathway opens up additional possibilities of understanding how migrating neurons are controlled.Neuronal positioning in the cortex is a genetically determined paradigm highly conserved among mammals. Therefore, accumulated molecular information both from human and mouse allowed initially the identification of many key players in this process, followed by the rudimentary positioning of these molecules in genetic pathways (reviewed in ref. 1). One of the major challenges in the field is to uncover physiologically relevant pathways that initiate at receptor activation, affect intracellular signal transduction, and are translated to neuronal movement coupled with target recognition and circuit formation. MODES OF RADIAL MIGRATIONThe advent of time-lapse imaging has changed our view regarding how cortical neurons migrate radially. Previous studies have pointed to the fact that neurons migrating along radial glia have a distinct morphology, with a growth-cone-like structure frequently present at the end of the leading process. [2][3][4][5] Time-lapse studies have indicated that each migrating neuron undergoes a series of cellular morphology changes, 5-7 (reviewed in refs. 8,9). More specifically three different modes of movement have been defined: somal translocation, cellular locomotion, 5 and a multipolar mode. 7 Somal translocation is defined by the translocation of the entire cell body. The leading process is frequently branched, with retractions following pauses. In case of cellular locomotion, the cells have a distinct morphology resembling features of glial-guided migrating neurons. The former is the prevalent form of radial movement of the early-born cortical neurons, while the latter is adopted by those generated later in corticogenesis (reviewed in ref. 10). The third mode of multipolar radial migration is quite different from the other two. These multipolar neurons extend numerous thin processes in various directions independently of the radial glial fibers. They do not exhibit fixed cell polarity, and ...

Missense mutations resulting in type 1 lissencephaly

“…Such is the case for the mammalian homolog of NudC, a protein that controls the levels of NudF in Aspergillus nidulans [32], and was shown to interact with LIS1 [33]. This is consistent with a similarity of mechanism between nuclear movement in the fungus and neuronal migration in the brain, since nuclear or somal translocation is one of the three main types of radial migration during the neocorticogenesis (reviewed by [34]). A tight relationship between LIS1 and microtubule (MT) regulation and MT-based motor proteins has been suggested for many organisms.…”

“…Protein phosphorylation is a way to control transient protein interactions, which are typically used in signal transduction pathways. Recently, phosphorylation of DCX by at least three different kinases was demonstrated; JNK [93], Cdk5 [115], protein kinase A (PKA) and/or the MARK/PAR-1 family of protein kinases [116] (reviewed by [34,117]). JNK phosphorylates DCX on at least three different sites, T321, T331 and S334 [93].…”

Polarity Regulation in Migrating Neurons in the Cortex

“…Lissencephaly and SBH have been observed in different regions of the same brain, defining an 'agyria-pachygyriaband' spectrum [15]. Both LIS1 and DCX affect microtubule dynamics [16][17][18], and their activity is regulated by phosphorylation [19][20][21]. Regulation of microtubules is thus likely to be an important feature in migrating neurons of the developing brain.…”

“…The MAPs LIS1 and DCX, which play a vital role in neuronal migration, have been the focus of intensive study during recent years [6,20,[115][116][117][118][119]. LIS1 interacts with tubulin and can modulate MT dynamics in vitro.…”

Ethanol–BDNF interactions: Still more questions than answers

“…This is isozyme-specific and JNKs can also participate in neuronal differentiation through phosphorylation of cytoskeletal proteins involved in neuronal migration (Reiner et al, 2004;Hirai et al, 2006) and axon formation (Oliva et al, 2006). p46 JNK is also activated by BDNF (Davis and Hassoun, unpublished observations).…”