Evidence for the Role of MAP1B in Axon Formation

Abstract

Cultured neurons obtained from a hypomorphous MAP1B mutant mouse line display a selective and significant inhibition of axon formation that reflects a delay in axon outgrowth and a reduced rate of elongation. This phenomenon is paralleled by decreased microtubule formation and dynamics, which is dramatic at the distal axonal segment, as well as in growth cones, where the more recently assembled microtubule polymer normally predominates. These neurons also have aberrant growth cone formation and increased actin-based protrusive activity. Taken together, this study provides direct evidence showing that by promoting microtubule dynamics and regulating cytoskeletal organization MAP1B has a crucial role in axon formation. INTRODUCTIONNeurons are highly polarized cells that contain a single long axon and multiple dendrites. Polarization occurs when one of the multiple neurites emerging from the cell body initiates a phase of rapid elongation, becoming the axon; the remaining neurites will develop as dendrites Dotti, 1997, 1999;Dotti et al., 1998). Because microtubule assembly and stabilization play an essential role in axon formation (Mitchison and Kirschner, 1989) a great deal of attention has been devoted to identify factors controlling microtubule organization and dynamics in nerve cells. Current evidence favors the view that several of the distinctive properties of neuronal microtubules, such as increased stability and spatial differentiation, arise from the developmentally regulated expression of structural microtubule-associated proteins (MAPs), which are notably abundant in neurons (Maccioni and Cambiazo, 1995). Therefore, it is likely that the expression of these proteins along neuronal development may affect neuronal polarization.MAP1B (Bloom et al., 1995) is the first MAP that is specifically expressed during neural development and that is especially prominent in neurons that are actively extending axons (Calvert and Anderton, 1985;Garner et al., 1990;Fischer and Romano-Clarke, 1991;Ulloa et al., 1993;Black et al., 1994: DiTella et al., 1996Gordon-Weeks and Fischer, 2000). These findings led to the hypothesis that MAP1B might be involved in axon formation by regulating microtubule dynamics. Evidence in favor of this proposal came from antisense experiments showing that MAP1B suppression reduces laminin-promoted axonal elongation (DiTella et al., 1996) and neurite outgrowth in PC12 cells (Brugg et al., 1993). More recently, it was shown that in Drosophila, an MAP1B-like protein is required for proper axonal and dendritic development Roos et al., 2000), and that microscale chromophore-assisted laser inactivation of phosphorylated MAP1B altered growth cone turning behavior in cultured neurons (Mack et al., 2000). The generation of MAP1B mutant mice has also provided additional important information. Despite discrepancies concerning the severity of the effects, all studies demonstrate that MAP1B-deficient mice have an impairment of brain development (Edelman et al., 1996;Takei et al., 1997; GonzalezBillault et...

Sustained GSK3 activity markedly facilitates nerve regeneration

“…MAP1B exists in at least two different modes of phosphorylation 41 , with mode II phosphorylation being mediated mainly by casein kinase II (refs 41,42) and occurring throughout the whole neuron. In contrast, mode I phosphorylation of MAP1B is concentrated in the distal part of the axon 43 and switches microtubules into a dynamic state by promoting tyrosination of a-tubulin 40,44 . Active GSK3 has been described to mediate this mode I phosphorylation at the two non-primed sites Serine 1,260 and Threonine 1,265 (refs 14,22,36).…”

“…In the developing nervous system, GSK3 regulates the activity of several microtubule associated proteins (MAPs) 4,13,[21][22][23]38,39 and thereby controls directed growth cone advancement and guidance. One of these proteins is MAP1B, which is required for axon growth 40 . MAP1B exists in at least two different modes of phosphorylation 41 , with mode II phosphorylation being mediated mainly by casein kinase II (refs 41,42) and occurring throughout the whole neuron.…”

Microtubule‐associated protein 1B: Novel paraneoplastic biomarker

“…20,21 MAP1B expression peaks during early stages of neuronal development [22][23][24][25][26][27][28] and plays an important role in neuronal differentiation, including dendritic spine formation and synaptic maturation. [29][30][31][32][33][34][35][36] In the adult brain, MAP1B is retained in areas with high synaptic plasticity. 37 The delayed nervous system development, abnormal neuronal morphology, lack of corpus callosum, and susceptibility to perinatal death in mice with genetically deleted MAP1B support its central role in neuronal development.…”

Expression changes of microtubule associated protein 1B in the brain of Fmr1 knockout mice

“…It controls neurite extension and growth cone motility via modulating microtubule dynamics [5,11,12] . MAP1B expresses at a higher level during embryogenesis.…”