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 as guidance cues for growth cones by remodeling actin cytoskeleton. Neurotrophins (NGF, BDNF, NT-3 and NT-4/5) bind to two structurally unrelated receptors, tyrosine kinase Trk receptors (TrkA, TrkB and TrkC), and Tumor necrosis factor receptor superfamily member 16 (NGFR(TNFRSF16)). Trk receptors and NGFR(TNFRSF16) are closely associated in cellular membranes.

Actin dynamics is controlled by Rho GTPases, which, in turn, are regulated by opposing effects of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). GAP p200RhoGAP, which is constitutively associated with TrkA, inhibits RhoA activity, which leads to neurite outgrowth [1], [2]. GEF RASGRF1, that is phosphorylated and activated by TrkA, TrkB, and TrkC, stimulates RhoA activity, followed by inhibition of neurite outgrowth [3]. RhoA downstream effector ROCK kinases directly phosphorylate kinase LIMK1, which, in turn, phosphorylates Cofilin that exhibits actin-depolymerizing activity [4], [5]. Activated ROCK kinases subsequently inactivate myosin light chain phosphatase (MLCP) by phosphorylation [6], which attenuates 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 to sialylated glycoconjugates (via N-acetyl-neuraminic acid) and mediates certain myelin-neuron cell-cell interactions. MAG, expressed by oligodendrocytes and Schwann cells in the nervous system, is important for maintaining the integrity of the myelin sheath.

Binding of MAG to the NGFR(TNFRSF16), as well as its binding to N-acetyl-neuraminic acid, gangliosides GD1a and GT1b on neuronal cells results in activation of NGFR(TNFRSF16), that is associated with ganglioside GT1b [8], [9]. MAG binding to NGFR(TNFRSF16) promotes ADAM metallopeptidase domain 17 (ADAM17) - mediated ectodomain shedding that generates NGFR(TNFRSF16) C-terminal fragment NGFR (CTF). Gamma-Secretase complex cleaves NGFR (CTF) and liberates NGFR(TNFRSF16) intracytoplasmic domain NGFR (ICD) [10], [11]. NGFR (ICD) sequesters Rho GDP dissociation inhibitor (GDI) alpha (RhoGDI alpha) that leads to RhoA activation [12], [13], [14]. These interactions induce RhoA, stimulation of ROCK kinases, actomyosin fibers formation, and inhibition of neurite outgrowth.

MAG can also bind to Nogo receptor (RTN4R) in a sialic-acid-independent manner. This interaction is functionally important for MAG-dependent neurite inhibition. RTN4R plays central role in mediating growth-inhibitory activities of myelin-derived proteins. Inhibitory protein Reticulon 4 and oligodendrocyte myelin glycoprotein (OMgp) bind to RTN4R to inhibit axonal outgrowth [15]. Lingo1, a nervous system-specific transmembrane protein, binds to RTN4R and NGFR(TNFRSF16) , which is an additional functional component of RTN4R/ NGFR(TNFRSF16) signaling complex [16]. Thus, MAG-dependent inhibition of neurite outgrowth depends on the complex molecular interaction between MAG, ganglioside GT1b, NGFR(TNFRSF16) , Lingo1 and RTN4R [17].

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