The RhoA‐associated protein Citron‐N controls dendritic spine maintenance by interacting with spine‐associated Golgi compartments

Camera, Paola; Schubert, Vanessa; Pellegrino, Maurizio; Berto, Gaia; Vercelli, Alessandro; Muzzi, Patrizia; Hirsch, Emilio; Altruda, Fiorella; Dotti, Carlos G.; Cunto, Ferdinando Di

doi:10.1038/embor.2008.21

Cited by 18 publications

(21 citation statements)

References 12 publications

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“…Moreover, phosphodiesterase 4D (PDE4D) a major regulator of cAMP levels, which is decreased in Disc1 mutant mice (Kvajo et al, 2011), is also associated with the Golgi apparatus (Verde et al, 2001), raising the possibility that Disc1 may be part of macromolecular complexes regulating cAMP in this cellular compartment. Importantly, the Golgi apparatus and post-Golgi trafficking have critical roles in dendrite and axonal growth, and spine morphogenesis (Horton et al, 2005; Rosso et al, 2004; Camera et al, 2008). Thus, Disc1-mediated impairments in aspects of Golgi-related metabolism may adversely affect dendritic growth.…”

Section: Discussionmentioning

confidence: 99%

A Disc1 mutation differentially affects neurites and spines in hippocampal and cortical neurons

Lepagnol-Bestel

Kvajo

Karayiorgou

et al. 2013

Molecular and Cellular Neuroscience

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A balanced chromosomal translocation segregating with schizophrenia and affective disorders in a large Scottish family disrupting DISC1 implicated this gene as a susceptibility gene for major mental illness. Here we study neurons derived from a genetically engineered mouse strain with a truncating lesion disrupting the endogenous Disc1 ortholog. We provide a detailed account of the consequences of this mutation on axonal and dendritic morphogenesis as well as dendritic spine development in cultured hippocampal and cortical neurons. We show that the mutation has distinct effects on these two types of neurons, supporting a cell-type specific role of Disc1 in establishing structural connections among neurons. Moreover, using a validated antibody we provide evidence indicating that Disc1 localizes primarily to Golgi apparatus-related vesicles. Our results support the notion that in vitro cultures derived from Disc1Tm1Kara mice provide a valuable model for future mechanistic analysis of the cellular and biochemical effects of this mutation, and can thus serve as a platform for drug discovery efforts.

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Section: Discussionmentioning

confidence: 99%

A Disc1 mutation differentially affects neurites and spines in hippocampal and cortical neurons

Lepagnol-Bestel

Kvajo

Karayiorgou

et al. 2013

Molecular and Cellular Neuroscience

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“…Moreover, we used a pSuper-based shRNA vector, which has been previously described, together with the appropriate control (Camera et al , 2008). HeLa cells plated on six-well plate were transfected using 1 μg of the required plasmid DNA and 3 μl Trans- IT-LT1 transfection reagent (Mirus Bio, Madison, WI), or 6.25 μl of the required siRNA (20 μM) and 2.5 μl Lipofectamine 2000 (Invitrogen, Carlsbad, CA), according to the manufacturers’ instructions.…”

Section: Methodsmentioning

confidence: 99%

Citron kinase controls abscission through RhoA and anillin

Gai

Camera

Dema

et al. 2011

MBoC

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“…Here, we have shown that the increased expression and activation of rhoA by obscurin's rhoGEF domain increases ROCK1 expression and decreases CRIK expression. ROCK1 activity in striated muscle is associated with hypertrophy and myoblast fusion (Maekawa et al, 1999;Liu et al, 2003;Nishiyama et al, 2004;Castellani et al, 2006;Peters and Michel, 2007), whereas CRIK activity is associated with cytokinesis and Golgi organization (Camera et al, 2003(Camera et al, , 2008Shandala et al, 2004;Berto et al, 2007). RhoA signaling through ROCK1 is a well-characterized pathway that is up-regulated in cardiac hypertrophy, and is responsible for many of the associated morphological changes (Molkentin and Dorn, 2001;Ahuja et al, 2007;Peters and Michel, 2007).…”

Section: Downstream Signalingmentioning

confidence: 99%

The Rho-Guanine Nucleotide Exchange Factor Domain of Obscurin Activates RhoA Signaling in Skeletal Muscle

Ford-Speelman

Roche

Bowman

et al. 2009

MBoC

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Obscurin is a large (ϳ800-kDa), modular protein of striated muscle that concentrates around the M-bands and Z-disks of each sarcomere, where it is well positioned to sense contractile activity. Obscurin contains several signaling domains, including a rho-guanine nucleotide exchange factor (rhoGEF) domain and tandem pleckstrin homology domain, consistent with a role in rho signaling in muscle. We investigated the ability of obscurin's rhoGEF domain to interact with and activate small GTPases. Using a combination of in vitro and in vivo approaches, we found that the rhoGEF domain of obscurin binds selectively to rhoA, and that rhoA colocalizes with obscurin at the M-band in skeletal muscle. Other small GTPases, including rac1 and cdc42, neither associate with the rhoGEF domain of obscurin nor concentrate at the level of the M-bands. Furthermore, overexpression of the rhoGEF domain of obscurin in adult skeletal muscle selectively increases rhoA expression and activity in this tissue. Overexpression of obscurin's rhoGEF domain and its effects on rhoA alter the expression of rho kinase and citron kinase, both of which can be activated by rhoA in other tissues. Injuries to rodent hindlimb muscles caused by large-strain lengthening contractions increases rhoA activity and displaces it from the M-bands to Z-disks, similar to the effects of overexpression of obscurin's rhoGEF domain. Our results suggest that obscurin's rhoGEF domain signals at least in part by inducing rhoA expression and activation, and altering the expression of downstream kinases in vitro and in vivo. INTRODUCTIONThe three largest proteins of the sarcomere, titin, nebulin, and obscurin, are critical for the assembly of myofibrils and the structural integrity of the sarcomere. The organization of actin and myosin in the mature myofibril is regulated by nebulin and titin, respectively, but the functions of obscurin, the most recently discovered of the three, are still poorly understood. An orthologue of Unc89 (Benian et al., 1996;Sutter et al., 2004), obscurin was first identified in mammals as a ligand of titin. Like titin, it is a multidomain protein (Young et al., 2001) composed largely of immunoglobulinlike (Ig) domains, which, with two fibronectin-like III (FnIII) domains, comprise its N-terminal and central regions. In the A isoform of obscurin, the C-terminal region of obscurin contains a calmodulin-binding (IQ) motif, followed by several Ig domains, a Src homology (SH) 3 domain, a rhoguanine nucleotide exchange factor (rhoGEF) domain, and tandem pleckstrin homology (PH) domain, two more Ig domains, and some nonmodular sequence. The nonmodular region at the extreme carboxy terminus includes several putative phosphorylation sites for extracellular signal-regulated kinase (ERK) kinases, as well as a binding site for a small, integral membrane form of ankyrin that concentrates in the network sarcoplasmic reticulum (nSR) (Young et al., 2001;Russell et al., 2002;Bagnato et al., 2003; KontrogianniKonstantopoulos et al., 2003;Borzok et al., 2007). This ...

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The RhoA‐associated protein Citron‐N controls dendritic spine maintenance by interacting with spine‐associated Golgi compartments

Cited by 18 publications

References 12 publications

A Disc1 mutation differentially affects neurites and spines in hippocampal and cortical neurons

A Disc1 mutation differentially affects neurites and spines in hippocampal and cortical neurons

Citron kinase controls abscission through RhoA and anillin

The Rho-Guanine Nucleotide Exchange Factor Domain of Obscurin Activates RhoA Signaling in Skeletal Muscle

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