scholarly journals Deficits Associated With Loss of STIM1 in Purkinje Neurons Including Motor Coordination Can Be Rescued by Loss of Septin 7

Author(s):  
Sreeja Kumari Dhanya ◽  
Gaiti Hasan

Septins are cytoskeletal proteins that can assemble to form heteromeric filamentous complexes and regulate a range of membrane-associated cellular functions. SEPT7, a member of the septin family, functions as a negative regulator of the plasma membrane–localized store-operated Ca2+ entry (SOCE) channel, Orai in Drosophila neurons, and in human neural progenitor cells. Knockdown of STIM, a Ca2+ sensor in the endoplasmic reticulum (ER) and an integral component of SOCE, leads to flight deficits in Drosophila that can be rescued by partial loss of SEPT7 in neurons. Here, we tested the effect of reducing and removing SEPT7 in mouse Purkinje neurons (PNs) with the loss of STIM1. Mice with the complete knockout of STIM1 in PNs exhibit several age-dependent changes. These include altered gene expression in PNs, which correlates with increased synapses between climbing fiber (CF) axons and Purkinje neuron (PN) dendrites and a reduced ability to learn a motor coordination task. Removal of either one or two copies of the SEPT7 gene in STIM1KO PNs restored the expression of a subset of genes, including several in the category of neuron projection development. Importantly, the rescue of gene expression in these animals is accompanied by normal CF-PN innervation and an improved ability to learn a motor coordination task in aging mice. Thus, the loss of SEPT7 in PNs further modulates cerebellar circuit function in STIM1KO animals. Our findings are relevant in the context of identifying SEPT7 as a putative therapeutic target for various neurodegenerative diseases caused by reduced intracellular Ca2+ signaling.

Gene Therapy ◽  
2008 ◽  
Vol 16 (3) ◽  
pp. 349-358 ◽  
Author(s):  
I Rothenaigner ◽  
S Kramer ◽  
M Meggendorfer ◽  
A Rethwilm ◽  
R Brack-Werner

2001 ◽  
Vol 281 (6) ◽  
pp. H2559-H2567 ◽  
Author(s):  
G. C. Wellman ◽  
L. Cartin ◽  
D. M. Eckman ◽  
A. S. Stevenson ◽  
C. M. Saundry ◽  
...  

Elevated intracellular Ca2+([Ca2+]i) has been implicated in contractile and phenotypic changes in arterial smooth muscle during hypertension. This study examined the role of membrane potential and [Ca2+]i in altered gene expression in cerebral arteries of a rat (Dahl) genetic model of salt-sensitive hypertension. Cerebral arteries from hypertensive animals (Dahl salt-sensitive) exhibited a tonic membrane depolarization of ∼15 mV compared with normotensive (Dahl salt-resistant) animals. Consistent with this membrane depolarization, voltage-dependent K+currents were decreased in cerebral artery myocytes isolated from hypertensive animals. Arterial wall Ca2+ was elevated in cerebral arteries from hypertensive animals, an effect reversed by diltiazem, a blocker of voltage-dependent Ca2+ channels. This depolarization-induced increase in [Ca2+]i was associated with increased activation of the transcription factor, cAMP response element binding protein, and increased expression of the immediate early gene c-fos, both of which are reversed by acute exposure to the voltage-dependent Ca2+ channel blocker nisoldipine. This study provides the first information linking altered Ca2+handling to changes in gene expression in cerebral arteries during hypertension.


2003 ◽  
Vol 284 (4) ◽  
pp. C999-C1005 ◽  
Author(s):  
George D. Thorne ◽  
Richard J. Paul

Organ culture specifically inhibits vasorelaxation to acute hypoxia and preferentially decreases specific voltage-dependent K+channel expression over other K+ and Ca2+channel subtypes. To isolate further potential oxygen-sensing mechanisms correlated with altered gene expression, we performed differential display analysis on RNA isolated from control and cultured coronary arterial rings. We hypothesize that organ culture results in altered gene expression important for vascular smooth muscle contractility important to the mechanism of hypoxia-induced relaxation. Our results indicate a milieu of changes suggesting both up- and downregulation of several genes. The altered expression pattern of two positive clones was verified by Northern analysis. Subsequent screening of a porcine cDNA library indicated homology to the ryanodine receptor (RyR). RT-PCR using specific primers to the three subtypes of RyR shows an upregulation of RyR2 and RyR3 after organ culture. Additionally, the caffeine- and/or ryanodine-sensitive intracellular Ca2+store was significantly more responsive to caffeine activation after organ culture. Our data indicate that organ culture increases expression of specific RyR subtypes and inhibits hypoxic vasorelaxation. Importantly, ryanodine blunted hypoxic relaxation in control coronary arteries, suggesting that upregulated RyR might play a novel role in altered intracellular Ca2+ handling during hypoxia.


Genes ◽  
2016 ◽  
Vol 7 (10) ◽  
pp. 76 ◽  
Author(s):  
Jessica DeWitt ◽  
Nicole Grepo ◽  
Brent Wilkinson ◽  
Oleg Evgrafov ◽  
James Knowles ◽  
...  

2009 ◽  
Vol 178 (1) ◽  
pp. 15-23 ◽  
Author(s):  
Maja-Theresa Dieterlen ◽  
Florian Wegner ◽  
Sigrid C. Schwarz ◽  
Javorina Milosevic ◽  
Barbara Schneider ◽  
...  

2021 ◽  
Author(s):  
Engin Demirdizen ◽  
Ruslan Al-Ali ◽  
Ashwin Narayanan ◽  
Xueyuan Sun ◽  
Julianna Patricia Varga ◽  
...  

Oligodendrogliomas are a subtype of isocitrate dehydrogenase (IDH) mutant gliomas defined by the co-deletion of chromosome arms 1p and 19q. Although the somatic genomic alterations of oligodendrogliomas have been well described, transcriptional changes unique to these tumors are not well studied. Here, we identify Tripartite Motif Containing 67 (TRIM67), an E3 ubiquitin ligase with essential roles during neuronal development, as an oncogene distinctly upregulated in oligodendrogliomas. We characterize the function of TRIM67 using high throughput assays, including RNA sequencing, total lysate-mass spectrometry (MS) and co-immunoprecipitation (IP)-MS using human neural progenitor cells and patient-derived glioma tumorspheres constitutively overexpressing TRIM67. Our high throughput data suggest that TRIM67 overexpression alters the abundance of cytoskeletal proteins, which were validated by functional assays, including immunofluorescence (IF) staining, co-IP and western blotting (WB). Additionally, IF staining results indicate that TRIM67 ectopic expression induces formation of membrane blebs in glioma cells, which could be reverted with the nonmuscle class II myosin inhibitor blebbistatin and selective ROCK inhibitor fasudil. GTP pulldown and WB assays further indicate that Rho GTPase/ROCK2 signaling is altered upon TRIM67 ectopic expression. Phenotypically, TRIM67 expression resulted in higher cell motility in wound healing experiments, reduced cell adherence in adhesion assays, accelerated tumor growth and reduced survival in mouse orthotopic implantation models of an oligodendroglioma-derived patient tumorsphere line. Taken together, our results demonstrate that upregulated TRIM67 induces blebbing-based rounded cell morphology through Rho GTPase/ROCK-mediated signaling thereby contributing to glioma pathogenesis.


2007 ◽  
Vol 204 (2) ◽  
pp. 512-524 ◽  
Author(s):  
Lucy Anderson ◽  
Rowan M. Burnstein ◽  
Xiaoling He ◽  
Richard Luce ◽  
Rob Furlong ◽  
...  

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