MED: Neurosurgery Papers
Permanent URI for this collection
Browse
Recent Submissions
Item Capzb2 Interacts with β-Tubulin to Regulate Growth Cone Morphology and Neurite Outgrowth(Public Library of Science, 2009-10-6) Davis, David A.; Wilson, Meredith H.; Giraud, Jodel; Xie, Zhigang; Tseng, Huang-Chun; England, Cheryl; Herscovitz, Haya; Tsai, Li-Huei; Delalle, IvanaAn actin regulatory protein unexpectedly also controls microtubule polymerization during the formation and maintenance of cellular outgrowths in neurons. Capping protein (CP) is a heterodimer that regulates actin assembly by binding to the barbed end of F-actin. In cultured nonneuronal cells, each CP subunit plays a critical role in the organization and dynamics of lamellipodia and filopodia. Mutations in either α or β CP subunit result in retinal degeneration in Drosophila. However, the function of CP subunits in mammalian neurons remains unclear. Here, we investigate the role of the β CP subunit expressed in the brain, Capzb2, in growth cone morphology and neurite outgrowth. We found that silencing Capzb2 in hippocampal neurons resulted in short neurites and misshapen growth cones in which microtubules overgrew into the periphery and completely overlapped with F-actin. In searching for the mechanisms underlying these cytoskeletal abnormalities, we identified β-tubulin as a novel binding partner of Capzb2 and demonstrated that Capzb2 decreases the rate and the extent of tubulin polymerization in vitro. We mapped the region of Capzb2 that was required for the subunit to interact with β-tubulin and inhibit microtubule polymerization. A mutant Capzb2 lacking this region was able to bind F-actin and form a CP heterodimer with α2-subunit. However, this mutant was unable to rescue the growth cone and neurite outgrowth phenotypes caused by Capzb2 knockdown. Together, these data suggest that Capzb2 plays an important role in growth cone formation and neurite outgrowth and that the underlying mechanism may involve direct interaction between Capzb2 and microtubules. Author SummaryNeuronal growth, migration, and survival depend on the regulated formation of cellular outgrowths called neurites. Extension of normal neurites requires coordinated interactions between cytoskeletal networks made up of microfilaments (composed of F-actin) and microtubules (formed by tubulin) in structures called growth cones that form at the tips of growing neurites. Capping protein (CP) is a heterodimer that regulates F-actin assembly in a variety of cell types. Surprisingly, the neuronal CP β subunit, Capzb2, not only regulates F-actin assembly, but also inhibits microtubule polymerization by direct interaction with tubulin. We further show that this function of Capzb2 is required for establishment of the normal shape of growth cones and the appropriate length of neurites. Our data thus reveal an unexpected, dual role for CP in the regulation of both microfilaments and microtubules in neurons.Item Control of Activating Transcription Factor 4 (ATF4) Persistence by Multisite Phosphorylation Impacts Cell Cycle Progression and Neurogenesis*(American Society for Biochemistry and Molecular Biology, 2010-8-19) Frank, Christopher L.; Ge, Xuecai; Xie, Zhigang; Zhou, Ying; Tsai, Li-HueiOrganogenesis is a highly integrated process with a fundamental requirement for precise cell cycle control. Mechanistically, the cell cycle is composed of transitions and thresholds that are controlled by coordinated post-translational modifications. In this study, we describe a novel mechanism controlling the persistence of the transcription factor ATF4 by multisite phosphorylation. Proline-directed phosphorylation acted additively to regulate multiple aspects of ATF4 degradation. Stabilized ATF4 mutants exhibit decreased β-TrCP degron phosphorylation, β-TrCP interaction, and ubiquitination, as well as elicit early G1 arrest. Expression of stabilized ATF4 also had significant consequences in the developing neocortex. Mutant ATF4 expressing cells exhibited positioning and differentiation defects that were attributed to early G1 arrest, suggesting that neurogenesis is sensitive to ATF4 dosage. We propose that precise regulation of the ATF4 dosage impacts cell cycle control and impinges on neurogenesis.Item Cerebral Collateral Circulation in Carotid Artery Disease(Bentham Science Publishers Ltd., 2011-12-29) Romero, José R.; Pikula, Aleksandra; Nguyen, Thanh N.; Nien, Yih Lin; Norbash, Alexander; Babikian, Viken L.Carotid artery disease is common and increases the risk of stroke. However, there is wide variability on the severity of clinical manifestations of carotid disease, ranging from asymptomatic to fatal stroke. The collateral circulation has been recognized as an important aspect of cerebral circulation affecting the risk of stroke as well as other features of stroke presentation, such as stroke patterns in patients with carotid artery disease. The cerebral circulation attempts to maintain constant cerebral perfusion despite changes in systemic conditions, due to its ability to autoregulate blood flow. In case that one of the major cerebral arteries is compromised by occlusive disease, the cerebral collateral circulation plays an important role in preserving cerebral perfusion through enhanced recruitment of blood flow. With the advent of techniques that allow rapid evaluation of cerebral perfusion, the collateral circulation of the brain and its effectiveness may also be evaluated, allowing for prompt assessment of patients with acute stroke due to involvement of the carotid artery, and risk stratification of patients with carotid stenosis in chronic stages. Understanding the cerebral collateral circulation provides a basis for the future development of new diagnostic tools, risk stratification, predictive models and new therapeutic modalities. In the present review we discuss basic aspects of the cerebral collateral circulation, diagnostic methods to assess collateral circulation, and implications in occlusive carotid artery disease.