Journal
JOURNAL OF NEUROSCIENCE
Volume 35, Issue 7, Pages 2942-2958Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.5029-13.2015
Keywords
anterograde transport; cortical development; microtubule; migration; neurite extension
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Funding
- Multidisciplinary Program for Elucidating Brain Development from Molecules to Social Behavior
- Project Allocation Fund of the University of Fukui
- Strategic Research Program for Brain Sciences Integrated research on neuropsychiatric disorders from the Ministry of Education, Culture, Sports, Science and Technology of Japan
- Grants-in-Aid for Scientific Research [15K08151, 25293043, 26430036, 25670091] Funding Source: KAKEN
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Cell positioning and neuronal network formation are crucial for proper brain function. Disrupted-in-Schizophrenia 1 (DISC1) is anterogradely transported to the neurite tips, together with Lis1, and functions in neurite extension via suppression of GSK3 beta activity. Then, transported Lis1 is retrogradely transported and functions in cell migration. Here, we show that DISC1-binding zinc finger protein (DBZ), together with DISC1, regulates mouse cortical cell positioning and neurite development in vivo. DBZ hindered Ndel1 phosphorylation at threonine 219 and serine 251. DBZ depletion or expression of a double-phosphorylated mimetic form of Ndel1 impaired the transport of Lis1 and DISC1 to the neurite tips and hampered microtubule elongation. Moreover, application of DISC1 or a GSK3 beta inhibitor rescued the impairments caused by DBZ insufficiency or double-phosphorylated Ndel1 expression. We concluded that DBZ controls cell positioning and neurite development by interfering with Ndel1 from disproportionate phosphorylation, which is critical for appropriate anterograde transport of the DISC1-complex.
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