Hiroyuki Kamiguchi

Activation of the MAPK Signal Cascade by the Neural Cell Adhesion Molecule L1 Requires L1 Internalization

L1-mediated axon growth involves intracellular signaling, but the precise mechanisms involved are not yet clear. We report a role for the mitogen-activated protein kinase (MAPK) cascade in L1 signaling. L1 physically associates with the MAPK cascade components Raf-1, ERK2, and the previously identified p90 rsk in brain. In vitro, ERK2 can phosphorylate L1 at Ser1204 and Ser1248 of the L1 cytoplasmic domain. These two serines are conserved in the L1 family of cell adhesion molecules, also being found in neurofascin and NrCAM. The ability of ERK2 to phosphorylate L1 suggests that L1 signaling could directly regulate L1 function by phosphorylation of the L1 cytoplasmic domain. In L1-expressing 3T3 cells, L1 cross-linking can activate ERK2. Remarkably, the activated ERK localizes with endocytosed vesicular L1 rather than cell surface L1, indicating that L1 internalization and signaling are coupled. Inhibition of L1 internalization with dominant-negative dynamin prevents activation of ERK. These results show that L1-generated signals activate the MAPK cascade in a manner most likely to be important in regulating L1 intracellular trafficking.

Neural cell adhesion molecule L1: Signaling pathways and growth cone motility

The neural cell adhesion molecule L1 plays a key role in nervous system development including neuronal migration, neurite growth, and axonal fasciculation. L1 is expressed on most developing axons, and homophilic binding of L1 molecules on adjacent axons is likely to play a key role in axon extension. It is now well documented that a number of second‐messenger systems are involved in L1‐stimulated neurite growth in vitro. However, it is unclear how L1 homophilic or heterophilic binding trigger signals that regulate the mechanical forces that produce axon extension. In this report, we will review recent advances in understanding L1‐associated signals, L1 interactions with the cytoskeleton, and the molecular mechanisms underlying growth cone motility. J. Neurosci. Res. 49:1–8, 1997.

Role of L1 in Neural Development: What the Knockouts Tell Us ☆

Mutations in the cell adhesion molecule L1 cause severe developmental anomalies in the human nervous system. Recent descriptions of L1 gene knock-out mice from three research groups demonstrate that these mice are strikingly similar to humans with mutations in the L1 gene. In both humans and mice there are defects in the development of the corticospinal tract and cerebellar vermis, hydrocephalus, and impaired learning. The production of a viable animal model for X-linked hydrocephalus suggests that unanswerable questions posed by the human disease will finally be approachable using modern experimental methods.

Computed tomographic analysis of hemifacial spasm: narrowing of the posterior fossa as a possible facilitating factor for neurovascular compression.

Hemifacial spasm can be caused by vascular compression of the facial nerve at the root exit zone from the brainstem. Several case reports suggest that narrowing of the cerebellopontine angle cistern caused by Pagets disease, abnormal elevation of the petrous bone caused by hyperplasia, or contralateral acoustic neurinoma may increase the chance of vascular compression of the facial nerve. Therefore, posterior fossa narrowness has been evaluated in 34 patients with hemifacial spasm by measuring the petrous angle and pons diameter index to elucidate whether narrowing of the posterior fossa can act as a facilitating factor for neurovascular compression. The petrous angle in the hemifacial spasm group was significantly smaller than that in the control group, which consisted of 33 patients with an unruptured supratentorial aneurysm, and the pons diameter index in the hemifacial spasm group was significantly greater than that in the control group. These results indicate that the cerebellopontine angle cistern of patients with hemifacial spasm is narrower resulting in more crowded cranial nerves and vascular structures compared with patients without hemifacial spasm. The narrowness of the cerebellopontine angle cistern may be a possible factor in facilitating neurovascular compression in hemifacial spasm.

Interleukin-1β and tumor necrosis factor-α co-operatively enhance a novel trophic activity of astrocytes for pontine cholinergic neurons in vitro

Insulin and insulin-like growth factors (IGFs) are the only known trophic factors for pontine cholinergic neurons. The present study revealed that astrocyte-extract pretreated with IL-1β and TNF-α significantly enhanced choline acetyltransferase (ChAT) activity of the pontine neurons in the presence of a supramaximal dose of insulin, while various trophic factors including IGFs failed to increase the ChAT activity under the same culture conditions, suggesting that IL-1β and TNF-α co-operatively enhanced the expression of a novel trophic factor for pontine cholinergic neurons in astrocytes.