KBP interacts with SCG10, linking Goldberg-Shprintzen syndrome to microtubule dynamics and neuronal differentiation

• Type of Material: Article
• Authors: Maria M. Alves, University of Groningen; Grzegorz Burzynski, Emory University; Jean-Marie Delalande, Emory University; Jan Osinga, University of Groningen; Annemieke van der Goot, University of Groningen; Amalia M. Dolga, University of Groningen; Esther de Graaff, Erasmus Medical Center; Alice S. Brooks, Erasmus Medical Center; Marco Metzger, Universität Leipzig; Ulrich L. M. Eisel, University of Groningen; Iain Shepherd, Emory University; Bart J. L. Eggen, University of Groningen; Robert M. W. Hofstra, University of Groningen
• Language: English
• Date: 2010-07-09
• Publisher: Oxford Journals
• Publication Version: Final Published Version
• Copyright Statement: © The Author 2010. Published by Oxford University Press. All rights reserved.
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1093/hmg/ddq280
• Title of Journal or Parent Work: Human Molecular Genetics
• Volume: 19
• Issue: 18
• Start Page: 3642
• End Page: 3651
• Grant/Funding Information: This work was supported by the Graduate School of Medical Sciences (GUIDE) and the Jan Kornelis de Cock Stichting grant to M.M.A.
• Keywords: Humans; Stathmin; Animals; Carrier Proteins; Membrane Proteins; HeLa Cells; Calcium-Binding Proteins; Neurons; Disease Models, Animal; Serpins; NIH 3T3 Cells; Microtubule Proteins; PC12 Cells; Zebrafish Proteins; Protein Binding; Mice, Inbred C57BL; Hirschsprung Disease; Cells, Cultured; Craniofacial Abnormalities; Mice; Neurogenesis; Cell Line; Microtubules; Intracellular Signaling Peptides and Proteins; Rats
• Research Categories: Biology, Molecular; Biology, Cell; Biology, Microbiology; Biology, Neuroscience

Abstract

Goldberg-Shprintzen syndrome (GOSHS) is a rare clinical disorder characterized by central and enteric nervous system defects. This syndrome is caused by inactivating mutations in the Kinesin Binding Protein (KBP) gene, which encodes a protein of which the precise function is largely unclear. We show that KBP expression is upregulated during neuronal development in mouse cortical neurons. Moreover, KBP-depleted PC12 cells were defective in nerve growth factor-induced differentiation and neurite outgrowth, suggesting that KBP is required for cell differentiation and neurite development. To identify KBP interacting proteins, we performed a yeast twohybrid screen and found that KBP binds almost exclusively to microtubule associated or related proteins, specifically SCG10 and several kinesins. We confirmed these results by validating KBP interaction with one of these proteins: SCG10, a microtubule destabilizing protein. Zebrafish studies further demonstrated an epistatic interaction between KBP and SCG10 in vivo. To investigate the possibility of direct interaction between KBP and microtubules, we undertook co-localization and in vitro binding assays, but found no evidence of direct binding. Thus, our data indicate that KBP is involved in neuronal differentiation and that the central and enteric nervous system defects seen in GOSHS are likely caused by microtubule-related defects.