title: Genetic deletion of Rnd3 results in aqueductal stenosis leading to hydrocephalus through up-regulation of Notch signaling.
abstract: Rho family guanosine triphosphatase (GTPase) 3 (Rnd3), a member of the small Rho GTPase family, is involved in the regulation of cell actin cytoskeleton dynamics, cell migration, and proliferation through the Rho kinase-dependent signaling pathway. We report a role of Rnd3 in the pathogenesis of hydrocephalus disorder. Mice with Rnd3 genetic deletion developed severe obstructive hydrocephalus with enlargement of the lateral and third ventricles, but not of the fourth ventricles. The cerebral aqueducts in Rnd3-null mice were partially or completely blocked by the overgrowth of ependymal epithelia. We examined the molecular mechanism contributing to this Rnd3-deficiency-mediated hydrocephalus and found that Rnd3 is a regulator of Notch signaling. Rnd3 deficiency, through either gene deletion or siRNA knockdown, resulted in a decrease in Notch intracellular domain (NICD) protein degradation. However, there was no correlated change in mRNA change, which in turn led to an increase in NICD protein levels. Immunoprecipitation analysis demonstrated that Rnd3 and NICD physically interacted, and that down-regulation of Rnd3 attenuated NICD protein ubiquitination. This eventually enhanced Notch signaling activity and promoted aberrant growth of aqueduct ependymal cells, resulting in aqueduct stenosis and the development of congenital hydrocephalus. Inhibition of Notch activity rescued the hydrocephalus disorder in the mutant animals.
authors: Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX 77030, USA.
authors: Xi
authors: X
authors: Lin
authors: Baohui
authors: B
authors: Liu
authors: Xiangsheng
authors: X
authors: Yang
authors: Xiaojing
authors: X
authors: Yue
authors: Lixia
authors: L
authors: Diao
authors: Jing
authors: J
authors: Wang
authors: Jiang
authors: J
authors: Chang
mesh_terms: D000818:Animals; D001921:Brain / Q000002:abnormalities; D004805:Ependyma / Q000166:cytology* / Q000378:metabolism; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D057809:HEK293 Cells; D006801:Humans; D006849:Hydrocephalus / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D011499:Protein Processing, Post-Translational; D034741:RNA, Small Interfering / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; D051880:Receptors, Notch; C513341:Rnd3 protein, mouse; C508705:RND3 protein, human; D020741:rho GTP-Binding Proteins
keywords: developmental brain defect; genetic mouse model; post-translational modification
references: J Biol Chem. 2002 Mar 15;277(11):8763-6
references: 11809764
references: Nat Rev Mol Cell Biol. 2003 Jun;4(6):446-56
references: 12778124
references: J Biol Chem. 2003 Jun 20;278(25):23196-203
references: 12682059
references: Microsc Res Tech. 2001 Mar 1;52(5):591-607
references: 11241868
references: Scan Electron Microsc. 1979;(3):335-40
references: 524006
references: Physiology (Bethesda). 2009 Apr;24:117-26
references: 19364914
references: Cell. 2006 Dec 15;127(6):1253-64
references: 17174898
references: Mol Cell Biol. 2012 Jan;32(2):297-308
references: 22106411
references: Annu Rev Cell Dev Biol. 2011;27:653-79
references: 21801012
references: Genes Dev. 2004 Mar 1;18(5):559-71
references: 15037549
references: PLoS One. 2011 Apr 28;6(4):e19236
references: 21552537
references: Mol Cell Biol. 2004 Sep;24(18):7829-40
references: 15340047
references: Proc Natl Acad Sci U S A. 2011 Dec 27;108(52):21117-21
references: 22160720
references: Prostate. 2005 Sep 1;64(4):332-40
references: 15754346
references: J Neurol. 2006 Oct;253(10):1255-66
references: 16773266
references: Mol Cell Biol. 2003 Jun;23(12):4219-29
references: 12773565
references: Neuron. 2011 Mar 24;69(6):1069-84
references: 21435554
references: Proc Natl Acad Sci U S A. 2004 Oct 26;101(43):15446-51
references: 15494444
references: Curr Biol. 2006 Dec 19;16(24):2466-72
references: 17174923
references: Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):2853-8
references: 18287022