Schwann cell myelin is comprised of compacted membrane regions and cytoplasmic regions with non-compacted membrane. While adherens junctions (AJ) are abundant in non-compact regions, their role in the myelination process is largely undefined. To explore this issue, a small inhibitory hairpin RNA directed against p120ctn has been delivered using adenovirus infection of Schwann cells at early stages of myelination in vivo. With strong and specific reduction in p120ctn levels for over 2 months, (a) the adherens junctions of the infected cells were reduced in size and immature with respect to recruitment of alpha-catenin; and (b) the formation of Schmidt-Lanterman incisures was prevented and there was a marked reduction in the thickness of the myelin sheath without a change in internodal length. These data show that p120ctn is necessary in the myelinating Schwann cell for the formation of mature adherens junctions and a normal myelin sheath.