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. 2020 Aug 14:13:150.
doi: 10.3389/fnmol.2020.00150. eCollection 2020.

Neuronal Signaling Involved in Neuronal Polarization and Growth: Lipid Rafts and Phosphorylation

Michihiro Igarashi  1 , Atsuko Honda  1 , Asami Kawasaki  1 , Motohiro Nozumi  1
Affiliations

Neuronal Signaling Involved in Neuronal Polarization and Growth: Lipid Rafts and Phosphorylation

Michihiro Igarashi et al. Front Mol Neurosci. .

Abstract

Neuronal polarization and growth are developmental processes that occur during neuronal cell differentiation. The molecular signaling mechanisms involved in these events in in vivo mammalian brain remain unclear. Also, cellular events of the neuronal polarization process within a given neuron are thought to be constituted of many independent intracellular signal transduction pathways (the "tug-of-war" model). However, in vivo results suggest that such pathways should be cooperative with one another among a given group of neurons in a region of the brain. Lipid rafts, specific membrane domains with low fluidity, are candidates for the hotspots of such intracellular signaling. Among the signals reported to be involved in polarization, a number are thought to be present or translocated to the lipid rafts in response to extracellular signals. As part of our analysis, we discuss how such novel molecular mechanisms are combined for effective regulation of neuronal polarization and growth, focusing on the significance of the lipid rafts, including results based on recently introduced methods.

Keywords: JNK; growth cone; lipid rafts; palmitoylation; phosphoproteomics; super-resolution microscopy.

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Figures

Figure 1
Figure 1
The lipid raft domain. Lipid rafts are composed of sphingolipids such as glycolipids and sphingomyelin (SM), cholesterol, and glycosylated phospholipid (GPI)-anchored or palmitoylated membrane proteins. Lipid rafts are thought to be interspersed among non-raft domains that are composed of the glycerophospholipids and exhibit high fluidity. The lower fluidity of the lipid rafts is presumed to lead to retention and localized concentration of membrane proteins that participate in signal transduction in response to extracellular signals.
Figure 2
Figure 2
Lipid rafts may be the site of signaling for the determination of the neuronal polarity. (A) The polarity of each neuron is probably not determined in an inconsistent way (upper) but instead is synchronized in vivo by extracellular signals exchanged among neurons (lower). The lower mechanism is expected to shorten the time for polarity determination compared to the upper one. (B) Glycoprotein M6a (GPM6a) is palmitoylated and sorted to the lipid rafts in the neuronal plasma membrane. GPM6a is believed to be palmitoylated at cysteine clusters (located near the protein’s N-terminus) via a reaction catalyzed by the HIP14 or ZHHC17 palmitoyltransferases; modification would occur within the Golgi apparatus, and GPM6a then would be inserted into the lipid raft domains (Butland et al., 2014). Although the non-palmitoylated form of GPM6a is localized to non-raft domains of the plasma membrane, this form of GPM6a does not appear to mediate biological effects in response to extracellular signals (Honda et al., 2017a). (C) Laminin induces the assembly of signaling molecules downstream of GPM6a around lipid rafts, an event that contributes to the rapid determination of polarity (see Honda et al., 2017a). GPM6a, Rap2, and Tiam2 are present in the lipid rafts with Rufy3, an adaptor protein that acts as a linker between GPM6a and Rap2-Tiam2 (Honda et al., 2017a,b). Tiam2 is a guanine nucleotide exchange factor (GEF) that activates Rac and is expected to contribute to the rapid determination of polarity. Modified from Honda et al. (2017a).
Figure 3
Figure 3
Membrane trafficking in the growth cone, as revealed by super-resolution microscopy. F-actin-dependent endocytosis occurs in the peripheral (P-) domain of the growth cone. The leading edge protrudes as filopodia, which have dense F-actin bundles (red lines). F-actin-bundling for filopodial formation induces endorphin-mediated endocytosis (EME; ①; Nozumi et al., 2017). EME depends on F-actin located in the Z-axis direction (see Igarashi et al., 2018). GPM6a (the symbol “m” in blue), distributed in the lipid rafts, is endocytosed through EME. The EME-dependent vesicles move in a retrograde direction to the central (C-) domain of the growth cone (②). Classical clathrin-mediated endocytosis (CME) mainly occurs at the bottom of the growth cone membrane (GCM; ③).
Figure 4
Figure 4
JNK activity in the axon and its substrates for axonal growth. JNK is activated in the developing neurons (Hirai et al., ; Yamasaki et al., ; Coffey, 2014). (A) JNK-dependent substrates are sorted to the distal axon and the growth cone. Phosphorylated segments of GAP-43 (peptides pS96 and pT172) and MAP1B (peptides pS25 and pS1201) are sorted to the plasma membrane and the microtubules in the growth cone of the distal axon, respectively. These substrate proteins are phosphorylated by JNK in the cell bodies before undergoing anterograde axonal transport or are phosphorylated by JNK proximal to the growth cone area [see (A)]. See Kawasaki et al. (2018) and Ishikawa et al. (2019). (B) JNK may be distributed within the growing axons in one of three patterns: (Ba) only in the cell bodies, (Bb) only in the growth cone, or (Bc) in the whole neuron. Our experimental results indicate that (Ba) or (Bc) are more likely (Kawasaki et al., 2018).
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