Wade, A.; (2011) A novel role for activated leukocyte cell adhesion molecule (ALCAM) in neurotrophin signalling in neurons. Doctoral thesis , UCL (University College London).

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Abstract

The classical immunoglobulin family of cell adhesion molecules, known as the IgCAMs, have been characterised as having an important adhesive function at areas of cell-cell contact and from cell to extracellular matrix. Members of this family have been shown to participate in signal transduction and increasingly it seems that this could be a general feature of the IgCAM family rather than the exception. We aimed to determine whether IgCAMs that undergo retrograde axonal transport in neurons contribute to neuronal viability and co-operate with neurotrophin signalling. Activated Leukocyte Cell Adhesion Molecule (ALCAM) was identified in cells of immune system as the binding partner of the T-cell glycoprotein CD6, where it contributes to normal T-cell activation. Additionally ALCAM has been shown to have an important role in the nervous system, where it is involved in neuron pathfinding and development of the neuromuscular junction. We identified ALCAM as a protein associated with the axonal retrograde transport compartment containing neurotrophins and their receptors in primary ventral horn neurons. I found that ALCAM is bidirectionally transported in neurons, and predominantly cotransported with the neurotrophin receptor p75NTR toward the cell body. Furthermore, I found ALCAM could specifically potentiate neurotrophic signalling. ALCAM overexpression resulted in extension of longer neuritic processes in PC12 cells treated with nerve growth factor (NGF). The extracellular domain is both necessary and sufficient to potentiate NGF-induced neurite outgrowth, while the transmembrane and cytoplasmic domain have no effect. ALCAM overexpression only potentiated specific growth factor stimuli but had no effect on other pathways leading to differentiation or on undifferentiated PC12 cell morphology. In conclusion, ALCAM appears to synergise with NGF signalling to induce neuronal differentiation and may have a role in the nervous system not only as an adhesion molecule but also in neurotrophin signalling.

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