RT Journal Article
SR Electronic
T1 Doublecortin (DCX) Mediates Endocytosis of Neurofascin Independently of Microtubule Binding
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 7439
OP 7453
DO 10.1523/JNEUROSCI.5318-11.2012
VO 32
IS 22
A1 Chan Choo Yap
A1 Max Vakulenko
A1 Kamil Kruczek
A1 Bashir Motamedi
A1 Laura Digilio
A1 Judy S. Liu
A1 Bettina Winckler
YR 2012
UL http://www.jneurosci.org/content/32/22/7439.abstract
AB Doublecortin on X chromosome (DCX) is one of two major genetic loci underlying human lissencephaly, a neurodevelopmental disorder with defects in neuronal migration and axon outgrowth. DCX is a microtubule-binding protein, and much work has focused on its microtubule-associated functions. DCX has other reported binding partners, including the cell adhesion molecule neurofascin, but the functional significance of the DCX–neurofascin interaction is not understood. Neurofascin localizes strongly to the axon initial segment in mature neurons, where it plays a role in assembling and maintaining other axon initial segment components. During development, neurofascin likely plays additional roles in axon guidance and in GABAergic synaptogenesis. We show here that DCX can modulate the surface distribution of neurofascin in developing cultured rat neurons and thereby the relative extent of accumulation between the axon initial segment and soma and dendrites. Mechanistically, DCX acts via increasing endocytosis of neurofascin from soma and dendrites. Surprisingly, DCX increases neurofascin endocytosis apparently independently of its microtubule-binding activity. We additionally show that the patient allele DCXG253D still binds microtubules but is deficient in promoting neurofascin endocytosis. We propose that DCX acts as an endocytic adaptor for neurofascin to fine-tune its surface distribution during neuronal development.