Roles In Axonal Targeting And Termination Dendritic Arborization And Spine Growth

n-cadherin appears to influence axonal targeting by signaling lamina-specific termination and promoting outgrowth and fasciculation36-39. Specific adhesive interactions also may target axons, in a less traditional sense, by instructing the encroaching axons of projection neurons and interneurons to form boutons onto distinct subcellular regions of target neurons. For instance, basket cell axons do not restrict their termination to Purkinje cell axon initial segments in mice lacking an axosomatic gradient of the cell-adhesion molecule neurofascin40. Cadherins do not appear to serve in this capacity, since long-term expression of an extracellular domain deletion mutant (see Section 3) in hippocampal neurons does not alter the normal distribution of inhibitory and excitatory terminals onto target neurons41. However, transient transfections at either early or later stages of maturation do reduce terminal density15, indicating that cadherins contribute to normal synapse formation, in part, by promoting or stabilizing the initial contacts between axons and dendrites.

Cadherins appear to instruct morphogenesis and innervation of differentiating neurites concomitantly, since changes in cadherin expression also affect dendritic differentiation. A-cadherin overexpression in hippocampal neurons promotes branching, albeit modest, of the dendritic arbor, while arborization is reduced by overexpression of the soluble intracellular domain42. This reduced branching may result from the retraction of destabilized dendritic arbors, as appears to occur after knocking down the expression of Celsr2, the 7-pass transmembrane cadherin, in Purkinje cells43. Additionally, overexpressing extracellular domain deletion mutants causes dendritic spines to appear more elongated or spiky, similar to spines lacking F-actin15,44,45.

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