Wheeler, Ann; (2005) The role of Rho GTPases in regulation of macrophage motility and morphology. Doctoral thesis , UCL (University College London).

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Abstract

Rho GTPases are important regulators of cell motility and morphology. Mammals have three highly homologous Rho proteins, RhoA, RhoB and RhoC. The aim of this thesis was to determine whether individual isoforms of Rho have unique functions in the regulation of cell motility using primary bone marrow-derived macrophages (BMM) as a model system. BMMs were shown to express RhoA, RhoB but not RhoC. BMMs were analysed to determine the role of RhoA and RhoB in motility and morphology. A comparison between RhoA and RhoB-null was carried out using a combination of RhoB-null BMMs, and BMM treated with the pan Rho inhibitor C3-transferase and the Rho kinase inhibitor Y27632. RhoB-null BMMs moved faster and had a smaller spread area than wild-types. Whereas BMM treated with C3-transferase and Y27632 had reduced migration. The RhoB-null BMMs did not change shape following CSF-1 withdrawal unlike wild-type cells. Analysis of BMM spreading and adhesion revealed that deletion of RhoB caused defects in the initial stages of cell spreading and adhesion. Interestingly in RhoB-null BMMs the GTPase activity of RhoA and Rac1 and phosphorylation of their targets LIMK and MLC was decreased less in response to withdrawal of CSF-1 than in wildtype cells. This suggests that RhoB may be acting as a 'brake' for RhoA activity.

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