Models for the failure in myelination of small-diameter axons resulting from perturbed β1 integrin signaling. (a) The oligodendrocyte initially extends processes to reach large and small axons and then initiates myelination. Large axons are myelinated earlier than small axons. (b) Model I: an axonal signal proportional to the diameter and above a certain threshold is required to initiate myelination by the contacting glial cell. Due to the expression of dnβ1 integrin there is a reduction in the glial signaling in response to this signal, such that the signal initiated by some small axons will now not be above the required (threshold) level for myelination. By contrast, the large axons provide a signal that is significantly in excess of the threshold level and/or additional signals, and thus will not be affected by perturbation of integrin signaling. (c) Model II: myelinating tracts rich in small-diameter axons require more oligodendrocyte processes than those tracts rich in large axons. Small axons are, therefore, particularly susceptible to any failure of the oligodendrocyte to generate multiple processes for myelination, as might occur after perturbation of integrin signaling, leading to an impaired ability of the cell to reorganize the cytoskeleton. See text for a discussion of the evidence for and against the two models.