Role of citron kinase in dendritic morphogenesis of cortical neurons

Cunto, Ferdinando Di; Ferrara, Luciana; Curtetti, Roberta; Imarisio, Sara; Guazzone, Simona; Broccoli, Vania; Bulfone, Alessandro; Altruda, Fiorella; Vercelli, Alessandro; Silengo, Lorenzo

doi:10.1016/s0361-9230(03)00058-3

Cited by 18 publications

(22 citation statements)

References 35 publications

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“…By specifically knocking out CIT-K in mice, we previously showed that it is mainly required by proliferating precursors to complete cytokinesis (Di Cunto et al, 2000). However, by analyzing the same mouse line and N1E-115 neuroblastoma cells overexpressing wild-type and mutated CIT-K constructs, we also found that it may inhibit neuronal differentiation similarly to ROKs (Di Cunto et al, 2002). Here, we have found that this is also true in differentiating PC12 cells (supplementary material Fig.…”

Section: Discussionmentioning

confidence: 56%

“…In vivo, CIT-K is expressed at high levels in proliferating neuronal precursors and at lower levels in differentiating and differentiated neural cells (Di Cunto et al, 2002). On the other hand, CIT-N is mainly expressed by differentiating and differentiated nerve cells, where it has been associated to the Golgi (Camera et al, 2003) and to post synaptic densities (Furuyashiki et al, 1999;Zhang et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

“…Since we previously showed that CIT-K inhibits neurite outgrowth both in vitro and in vivo (Di Cunto et al, 2002), the interaction that we detected led us to investigate whether TTC3 might also be involved in this process. We overexpressed GFP-TTC3 constructs in PC12 cells, which were induced to differentiate into a neuronal-like phenotype after stimulation with the neurotrophin NGF (Vaudry et al, 2002).…”

Section: Ttc3 Inhibits the Morphologic Differentiation Induced By Ngfmentioning

confidence: 93%

“…CIT-K and CIT-N plasmids have been previously described (Camera et al, 2003;Di Cunto et al, 2002). The MYC-CBR construct was produced by PCR and cloning into the pcDNA3 vector (Invitrogen).…”

Section: Plasmidsmentioning

confidence: 99%

“…Indeed, mice lacking CIT-K display severe microcephaly (Di Cunto et al, 2000), caused by cytokinesis failure and apoptosis of the mentioned cell types. Moreover, CIT-K regulates the extension of neurites and dendrites, both in cultured neuroblastoma cells and in vivo (Di Cunto et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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The Down syndrome critical region protein TTC3 inhibits neuronal differentiation via RhoA and Citron kinase

Berto

Camera

Fusco

et al. 2007

Journal of Cell Science

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The Down syndrome critical region (DSCR) on Chromosome 21 contains many genes whose duplication may lead to the major phenotypic features of Down syndrome and especially the associated mental retardation. However, the functions of DSCR genes are mostly unknown and their possible involvement in key brain developmental events still largely unexplored. In this report we show that the protein TTC3, encoded by one of the main DSCR candidate genes, physically interacts with Citron kinase (CIT-K) and Citron N (CIT-N), two effectors of the RhoA small GTPase that have previously been involved in neuronal proliferation and differentiation. More importantly, we found that TTC3 levels can strongly affect the NGF-induced differentiation of PC12 cells, by a CIT-K-dependent mechanism. Indeed, TTC3 overexpression leads to strong inhibition of neurite extension, which can be reverted by CIT-K RNAi. Conversely, TTC3 knockdown stimulates neurite extension in the same cells. Finally, we find that Rho, but not Rho kinase, is required for TTC3 differentiation-inhibiting activity. Our results suggest that the TTC3–RhoA–CIT-K pathway could be a crucial determinant of in vivo neuronal development, whose hyperactivity may result in detrimental effects on the normal differentiation program.

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Section: Discussionmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Section: Ttc3 Inhibits the Morphologic Differentiation Induced By Ngfmentioning

confidence: 93%

Section: Plasmidsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Down syndrome critical region protein TTC3 inhibits neuronal differentiation via RhoA and Citron kinase

Berto

Camera

Fusco

et al. 2007

Journal of Cell Science

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Deletion of the citron kinase gene selectively affects the number and distribution of interneurons in barrelfield cortex

Muzzi

Camera²,

Cunto³

et al. 2009

J of Comparative Neurology

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Citron kinase (CIT-K), a ser/thr kinase, is required during neurogenesis for cytokinesis of neuronal precursors. Deletion of the cit-k gene in mice (cit-k(-/-) mice) leads to a severe malformative central nervous system syndrome characterized by microencephaly, ataxia, and epileptic seizures; affected mice die by the third week of postnatal life. We have used NADPH-diaphorase histochemistry, immunostaining for calbindin, calretinin, parvalbumin, and glutamic acid decarboxylase 67 (GAD67), and histological staining to undertake qualitative and quantitative analyses of the morphology and distribution of interneurons in the barrelfield cortex of cit-k(-/-) mice. By postnatal day 13, lack of CIT-K results in profoundly altered cortical cell morphology: the infragranular layers are populated by large, binucleate interneurons bearing many more dendrites than in control mice, an anatomical profile that has also been reported for the cortex of humans with cortical dysplasias and epilepsy. Tessellation analyses reveal that a clustered distribution of interneurons is maintained in cit-k(-/-) mice, but that their nearest neighbor distance is significantly increased, and thus their density is reduced; the overall number of interneurons is more dramatically decreased in the absence of CIT-K than would be predicted on the basis of the reduced brain size of affected mice. This reduction of inhibitory gamma-aminobutyric acid (GABA)ergic neurons likely underlies the occurrence of epileptic seizures in the cit-k(-/-) mice. Furthermore, the altered distribution of NADPH-diaphorase-positive interneurons could be responsible for an impaired coupling of cortical activity to blood flow, also affecting cortical growth and functioning.

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Genetic Analysis of Rho Protein Function in Mice

Sordella

Settleman

Proteins and Cell Regulation

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The Rho small GTPases regulate a variety of cellular functions, including proliferation, differentiation, vesicle trafficking, gene expression, adhesion, and motility. Among their well established essential roles is that of organizing the actin cytoskeleton, and this aspect of Rho GTPase function has led to the identification of important roles for various Rho family GTPases in a variety of actin-dependent cellular processes, including cell shape change, adhesion, and migration. As critical regulators of these actin-mediated processes, the Rho GTPases also function as essential regulators of many developmental processes. The morphogenesis of tissues in all developing multi-cellular organisms requires precise changes in cell shape and cell movements that depend on the various Rho GTPases. This has been observed in studies using sevefigureral different developmental model systems, including flies, worms, frogs, and mice. Here, we review the literature reporting functions for Rho GTPases and their associated signaling components in the context of embryonic development, adult physiology, and pathogenesis. In particular, the focus of the studies described here is on the mouse system, where transgenic and "knockout" strategies have played an especially important role in elucidating the in vivo organization and function of the various Rho signaling pathways.

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Role of citron kinase in dendritic morphogenesis of cortical neurons

Cited by 18 publications

References 35 publications

The Down syndrome critical region protein TTC3 inhibits neuronal differentiation via RhoA and Citron kinase

The Down syndrome critical region protein TTC3 inhibits neuronal differentiation via RhoA and Citron kinase

Deletion of the citron kinase gene selectively affects the number and distribution of interneurons in barrelfield cortex

Genetic Analysis of Rho Protein Function in Mice

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