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Molecular Brain
Published in: Molecular Brain 1/2016

Open Access 01-12-2016 | Research

RAB18, a protein associated with Warburg Micro syndrome, controls neuronal migration in the developing cerebral cortex

Authors: Qinwei Wu, Xiaqin Sun, Weihua Yue, Tianlan Lu, Yanyan Ruan, Tianda Chen, Dai Zhang

Published in: Molecular Brain | Issue 1/2016

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Abstract

Background

Loss of function mutations in RAB18, has been identified in patients with the human neurological and developmental disorder Warburg Micro syndrome. However, the function of RAB18 in brain remains unknown.

Results

In this study, we report that RAB18 is a critical regulator of neuronal migration and morphogenesis. Using in utero electroporation suppression of RAB18 in the mouse brain impairs radial migration. Overexpression of dominant negative RAB18 or disruption of RAB3GAP (RAB18GEF) also results in delayed neuronal migration in the developing mouse cortex and inhibition of neurite growth in vitro. Moreover, loss of RAB18 induces an acceleration of N-cadherin degradation by lysosomal pathway resulting in the decrease of surface level of N-cadherin on neurons.

Conclusions

RAB18 regulates neuronal migration and morphogenesis during development. Our findings highlight the critical role of RAB3GAP-RAB18 pathway in the developing cerebral cortex and might explain some of clinical features observed in patients with Warburg Micro syndrome.
Appendix
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Literature
1.
Warburg M, Sjo O, Fledelius HC, Pedersen SA. Autosomal recessive microcephaly, microcornea, congenital cataract, mental retardation, optic atrophy, and hypogenitalism, Micro syndrome. Am J Dis Child. 1993;147:1309–12.CrossRefPubMed
2.
Liegel RP, Handley MT, Ronchetti A, Brown S, Langemeyer L, Linford A, et al. Loss-of-function mutations in TBC1D20 cause cataracts and male infertility in blind sterile mice and Warburg micro syndrome in humans. Am J Hum Genet. 2013;93:1001–14.PubMedCentralCrossRefPubMed
3.
Bem D, Yoshimura S, Nunes-Bastos R, Bond FC, Kurian MA, Rahman F, et al. Loss-of-function mutations in RAB18 cause Warburg micro syndrome. Am J Hum Genet. 2011;88:499–507.PubMedCentralCrossRefPubMed
4.
Borck G, Wunram H, Steiert A, Volk AE, Korber F, Roters S, et al. A homozygous RAB3GAP2 mutation causes Warburg Micro syndrome. Hum Genet. 2011;129:45–50.CrossRefPubMed
5.
Aligianis IA, Morgan NV, Mione M, Johnson CA, Rosser E, Hennekam RC, et al. Mutation in Rab3 GTPase-activating protein (RAB3GAP) noncatalytic subunit in a kindred with Martsolf syndrome. Am J Hum Genet. 2006;78:702–7.PubMedCentralCrossRefPubMed
6.
Aligianis IA, Johnson CA, Gissen P, Chen D, Hampshire D, Hoffmann K, et al. Mutations of the catalytic subunit of RAB3GAP cause Warburg Micro syndrome. Nat Genet. 2005;37:221–3.CrossRefPubMed
7.
Handley MT, Morris-Rosendahl DJ, Brown S, Macdonald F, Hardy C, Bem D, et al. Mutation spectrum in RAB3GAP1, RAB3GAP2, and RAB18 and genotype-phenotype correlations in warburg micro syndrome and Martsolf syndrome. Hum Mutat. 2013;34:686–96.CrossRefPubMed
8.
Gerondopoulos A, Bastos RN, Yoshimura S, Anderson R, Carpanini S, Aligianis I, et al. Rab18 and a Rab18 GEF complex are required for normal ER structure. J Cell Biol. 2014;205:707–20.PubMedCentralCrossRefPubMed
9.
Handley MT, Carpanini SM, Mali GR, Sidjanin DJ, Aligianis IA, Jackson IJ, et al. Warburg Micro syndrome is caused by RAB18 deficiency or dysregulation. Open Biol. 2015;5:150047.PubMedCentralCrossRefPubMed
10.
Martin S, Driessen K, Nixon SJ, Zerial M, Parton RG. Regulated localization of Rab18 to lipid droplets: effects of lipolytic stimulation and inhibition of lipid droplet catabolism. J Biol Chem. 2005;280:42325–35.CrossRefPubMed
11.
Vazquez-Martinez R, Cruz-Garcia D, Duran-Prado M, Peinado JR, Castano JP, Malagon MM. Rab18 inhibits secretory activity in neuroendocrine cells by interacting with secretory granules. Traffic. 2007;8:867–82.CrossRefPubMed
12.
Ozeki S, Cheng J, Tauchi-Sato K, Hatano N, Taniguchi H, Fujimoto T. Rab18 localizes to lipid droplets and induces their close apposition to the endoplasmic reticulum-derived membrane. J Cell Sci. 2005;118:2601–11.CrossRefPubMed
13.
Dejgaard SY, Murshid A, Erman A, Kizilay O, Verbich D, Lodge R, et al. Rab18 and Rab43 have key roles in ER-Golgi trafficking. J Cell Sci. 2008;121:2768–81.CrossRefPubMed
14.
O'Mahony F, Wroblewski K, O'Byrne SM, Jiang H, Clerkin K, Benhammou J, et al. Liver X receptors balance lipid stores in hepatic stellate cells through Rab18, a retinoid responsive lipid droplet protein. Hepatology. 2015;62:615–26.CrossRefPubMed
15.
Falace A, Buhler E, Fadda M, Watrin F, Lippiello P, Pallesi-Pocachard E, et al. TBC1D24 regulates neuronal migration and maturation through modulation of the ARF6-dependent pathway. Proc Natl Acad Sci U S A. 2014;111:2337–42.PubMedCentralCrossRefPubMed
16.
Kawauchi T, Sekine K, Shikanai M, Chihama K, Tomita K, Kubo K, et al. Rab GTPases-dependent endocytic pathways regulate neuronal migration and maturation through N-cadherin trafficking. Neuron. 2010;67:588–602.CrossRefPubMed
17.
Takano T, Tomomura M, Yoshioka N, Tsutsumi K, Terasawa Y, Saito T, et al. LMTK1/AATYK1 is a novel regulator of axonal outgrowth that acts via Rab11 in a Cdk5-dependent manner. J Neurosci. 2012;32:6587–99.CrossRefPubMed
18.
Nakazawa H, Sada T, Toriyama M, Tago K, Sugiura T, Fukuda M, et al. Rab33a mediates anterograde vesicular transport for membrane exocytosis and axon outgrowth. J Neurosci. 2012;32:12712–25.CrossRefPubMed
19.
Kobayashi H, Fukuda M. Rab35 establishes the EHD1-association site by coordinating two distinct effectors during neurite outgrowth. J Cell Sci. 2013;126:2424–35.CrossRefPubMed
20.
Wang T, Liu Y, Xu XH, Deng CY, Wu KY, Zhu J, et al. Lgl1 activation of rab10 promotes axonal membrane trafficking underlying neuronal polarization. Dev Cell. 2011;21:431–44.CrossRefPubMed
21.
Cheng CY, Wu JC, Tsai JW, Nian FS, Wu PC, Kao LS, et al. ENU mutagenesis identifies mice modeling Warburg Micro Syndrome with sensory axon degeneration caused by a deletion in Rab18. Exp Neurol. 2015;267:143–51.CrossRefPubMed
22.
Wiegreffe C, Simon R, Peschkes K, Kling C, Strehle M, Cheng J, et al. Bcl11a (Ctip1) controls migration of cortical projection neurons through regulation of Sema3c. Neuron. 2015;87:311–25.CrossRefPubMed
23.
Wu QF, Yang L, Li S, Wang Q, Yuan XB, Gao X, et al. Fibroblast growth factor 13 is a microtubule-stabilizing protein regulating neuronal polarization and migration. Cell. 2012;149:1549–64.CrossRefPubMed
24.
La Fata G, Gartner A, Dominguez-Iturza N, Dresselaers T, Dawitz J, Poorthuis RB, et al. FMRP regulates multipolar to bipolar transition affecting neuronal migration and cortical circuitry. Nat Neurosci. 2014;17:1693–700.CrossRefPubMed
25.
Nagano F, Sasaki T, Fukui K, Asakura T, Imazumi K, Takai Y. Molecular cloning and characterization of the noncatalytic subunit of the Rab3 subfamily-specific GTPase-activating protein. J Biol Chem. 1998;273:24781–5.CrossRefPubMed
26.
Fukui K, Sasaki T, Imazumi K, Matsuura Y, Nakanishi H, Takai Y. Isolation and characterization of a GTPase activating protein specific for the Rab3 subfamily of small G proteins. J Biol Chem. 1997;272:4655–8.CrossRefPubMed
27.
Jossin Y, Cooper JA. Reelin, Rap1 and N-cadherin orient the migration of multipolar neurons in the developing neocortex. Nat Neurosci. 2011;14:697–703.PubMedCentralCrossRefPubMed
28.
Martire G, Mottola G, Pascale MC, Malagolini N, Turrini I, Serafini-Cessi F, et al. Different fate of a single reporter protein containing KDEL or KKXX targeting signals stably expressed in mammalian cells. J Biol Chem. 1996;271:3541–7.CrossRefPubMed
29.
Barr FA, Puype M, Vandekerckhove J, Warren G. GRASP65, a protein involved in the stacking of Golgi cisternae. Cell. 1997;91:253–62.CrossRefPubMed
30.
Fu AK, Hung KW, Fu WY, Shen C, Chen Y, Xia J, et al. APC(Cdh1) mediates EphA4-dependent downregulation of AMPA receptors in homeostatic plasticity. Nat Neurosci. 2011;14:181–9.CrossRefPubMed
31.
Kawauchi T, Chihama K, Nabeshima Y, Hoshino M. The in vivo roles of STEF/Tiam1, Rac1 and JNK in cortical neuronal migration. EMBO J. 2003;22:4190–201.PubMedCentralCrossRefPubMed
32.
33.
Kriegstein AR, Noctor SC. Patterns of neuronal migration in the embryonic cortex. Trends Neurosci. 2004;27:392–9.CrossRefPubMed
34.
LoTurco JJ, Bai JL. The multipolar stage and disruptions in neuronal migration. Trends Neurosci. 2006;29:407–13.CrossRefPubMed
35.
Evsyukova I, Plestant C, Anton ES. Integrative mechanisms of oriented neuronal migration in the developing brain. Annu Rev Cell Dev Biol. 2013;29:299–353.PubMedCentralCrossRefPubMed
36.
37.
Tsai JW, Chen Y, Kriegstein AR, Vallee RB. LIS1 RNA interference blocks neural stem cell division, morphogenesis, and motility at multiple stages. J Cell Biol. 2005;170:935–45.PubMedCentralCrossRefPubMed
38.
Ohshima T, Hirasawa M, Tabata H, Mutoh T, Adachi T, Suzuki H, et al. Cdk5 is required for multipolar-to-bipolar transition during radial neuronal migration and proper dendrite development of pyramidal neurons in the cerebral cortex. Development. 2007;134:2273–82.CrossRefPubMed
39.
Bai J, Ramos RL, Ackman JB, Thomas AM, Lee RV, LoTurco JJ. RNAi reveals doublecortin is required for radial migration in rat neocortex. Nat Neurosci. 2003;6:1277–83.CrossRefPubMed
40.
Zhao PP, Yao MJ, Chang SY, Gou LT, Liu MF, Qiu ZL, et al. Novel function of PIWIL1 in neuronal polarization and migration via regulation of microtubule-associated proteins. Mol Brain. 2015;8:39.PubMedCentralCrossRefPubMed
41.
Carpanini SM, McKie L, Thomson D, Wright AK, Gordon SL, Roche SL, et al. A novel mouse model of Warburg Micro Syndrome reveals roles for RAB18 in eye development and organisation of the neuronal cytoskeleton. Dis Model Mech. 2014;7:711-22.
42.
Ayalew M, Le-Niculescu H, Levey DF, Jain N, Changala B, Patel SD, et al. Convergent functional genomics of schizophrenia: from comprehensive understanding to genetic risk prediction. Mol Psychiatry. 2012;17:887–905.PubMedCentralCrossRefPubMed
43.
Metadata
Title
RAB18, a protein associated with Warburg Micro syndrome, controls neuronal migration in the developing cerebral cortex
Authors
Qinwei Wu
Xiaqin Sun
Weihua Yue
Tianlan Lu
Yanyan Ruan
Tianda Chen
Dai Zhang
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Molecular Brain / Issue 1/2016
Electronic ISSN: 1756-6606
DOI
https://doi.org/10.1186/s13041-016-0198-2

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