Development MAG-dependent inhibition of neurite outgrowth

MAG-dependent inhibition of neurite outgrowth

Neurotrophins are key regulators of the fate and shape of neuronal cells. They act asguidance cues for growth cones by remodeling actin cytoskeleton. Neurotrophins (NGF, BDNF, NT-3 and NT-4/5 ) bind to two structurallyunrelated receptors, tyrosine kinase Trk receptors ( TrkA, TrkB andTrkC ), and Tumor necrosis factor receptor superfamily member 16 ( NGFR).Trk receptors and NGFR are closely associated in cellular membranes.

Actin dynamics is controlled by Rho GTPases, which, in turn, are regulated byopposing effects of guanine nucleotide exchange factors (GEFs) and GTPase-activatingproteins (GAPs). GAP p200RhoGAP, which is constitutively associated withTrkA, inhibits RhoA activity, which leads to neurite outgrowth [1], [2]. GEF RASGRF1, that is phosphorylated and activated byTrkA, TrkB, and TrkC, stimulates RhoA activity, followedby inhibition of neurite outgrowth [3]. RhoA downstream effectorROCK kinases directly phosphorylate kinase LIMK1, which, in turn,phosphorylates Cofilin that exhibits actin -depolymerizing activity [4], [5]. Activated ROCK kinases subsequently inactivate myosinlight chain phosphatase ( MLCP ) by phosphorylation [6], whichattenuates myosin light chains ( MELC ) and myosin regulatory light chains (MRLC ) phosphorylation [7] and formation of actomyosin fibers. 

Myelin-associated protein ( MAG or siglec-4) is a lectin that binds tosialylated glycoconjugates (via N-acetyl-neuraminic acid ) and mediates certainmyelin-neuron cell-cell interactions. MAG, expressed by oligodendrocytes andSchwann cells in the nervous system, is important for maintaining the integrity of themyelin sheath.

Binding of MAG to the NGFR, as well as its binding toN-acetyl-neuraminic acid, gangliosides GD1a and GT1b onneuronal cells results in activation of NGFR, that is associated withganglioside GT1b [8], [9]. NGFR acts as adisplacement factor that releases RhoA from Rho GDP dissociation inhibitor (RhoGDI alpha ) [10]. These interactions induce activation ofRhoA, stimulation of ROCK kinases, actomyosin fibers formation, andinhibition of neurite outgrowth.

MAG can also bind to Nogo receptor ( RTN4R ) in asialic-acid-independent manner. This interaction is functionally important for MAG-dependent neurite inhibition. RTN4R plays central role in mediatinggrowth-inhibitory activities of myelin-derived proteins. Inhibitory protein Reticulon4 and oligodendrocyte myelin glycoprotein ( OMgp ) bind to RTN4R toinhibit axonal outgrowth [11]. Lingo1, a nervous system-specifictransmembrane protein, binds to RTN4R and NGFR, which is an additionalfunctional component of RTN4R/ NGFR signaling complex [12].Thus, MAG -dependent inhibition of neurite outgrowth depends on the complexmolecular interaction between MAG, ganglioside GT1b, NGFR,Lingo1 and RTN4R [13].

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