Doublecortin (DCX) Mediates Endocytosis of Neurofascin Independently of Microtubule Binding
Open accessAbstract
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.
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We detect changes in genes associated with myelination and synaptic vesicle endocytosis, including DCX, SCAP, RB1CC1, ADSL and PACSIN1.
“We also detect changes in genes associated with myelination and synaptic vesicle endocytosis, critical to sustain a high rate of synaptic transmission, including DCX104, SCAP105, RB1CC1106, ADSL107 and PACSIN1108 among others (Supplementary Information 2).”
From A catalog of single nucleotide changes distinguishing modern humans from archaic hominins (2019) · cites this paper as [104]
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A catalog of single nucleotide changes distinguishing modern humans from archaic hominins
Kuhlwilm, M., & Boeckx, C. (2019) · Scientific Reports · doi:10.1038/s41598-019-44877-x · Cited by 108 · see citing works
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- Authors
- Yap, C. C., Vakulenko, M., Kruczek, K., Motamedi, B., Digilio, L., Liu, J. S., & Winckler, B.
- Affiliations
- University of Virginia (US)
- Children's National (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2012-05-30
- Volume
- 32
- Issue
- 22
- Pages
- 7439-7453
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3372911
- OpenAlex
- W2145733791
- Cited by
- 45
- References
- 57
- Citations by year
- 2025: 3 · 2024: 2 · 2023: 2 · 2022: 5 · 2021: 1 · 2020: 5 · 2019: 4 · 2018: 2 · 2017: 1 · 2016: 2 · 2015: 7 · 2014: 5 · 2013: 5 · 2012: 1
- FWCI
- 1.94
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Miami
- National Institutes of Health
- Genentech
- National Institute of General Medical Sciences (R01GM086913)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- doublecortin, neurofascin, endocytosis, axon initial segment, lissencephaly, microtubule binding, neuronal development, surface distribution, axon guidance
- MeSH terms
- Doublecortin Domain Proteins, Doublecortin Protein, Animals, Cell Membrane, Cells, Cultured, Chlorocebus aethiops, Dendrites, Embryo, Mammalian, Endocytosis, Female, Gene Expression Regulation, Hippocampus, Humans, Male, Microtubule-Associated Proteins, Microtubules, Nerve Growth Factors, Neurons, Neuropeptides, Protein Binding, Time Factors, Transfection, Sodium Channels, Cell Adhesion Molecules, Cell Polarity, Point Mutation, Ankyrins, Statistics, Nonparametric, RNA, Small Interfering, Immunoprecipitation, Green Fluorescent Proteins, Rats, Lysosomal-Associated Membrane Protein 1
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