Guest, J.L.; (2004) Role of p21 activated kinase in zebrafish lateral line development. Doctoral thesis , University of London.

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Abstract

Migration of the posterior lateral line primordium is a process of directed response to a chemotactic signal. We have observed directional protrusions of the cells at the leading edge of migrating primordia. The p21 activated kinase (Pak) family of proteins are downstream effectors of the small GTPases Rac and Cdc42 and have been shown to play important roles in the regulation of cell adhesion and migration in many organisms. In order to understand the molecular mechanisms underlying directed cell migration in zebrafish we have identified and characterised two zebrafish pak2 genes {lcub}pak2a and pak2b) and found that their functions are important for migration of the lateral line primordium. Pak2a and Pak2b have similar protein sequences suggesting similar functions in development. Knock down of Pak2 using antisense morpholino oligonucleotides resulted in a variety of defects in zebrafish development including retarded migration of the posterior lateral line primordium and aberrant migration of primordial germ cells. Zebrafish pak2 genes may function by dynamically regulating the F-actin reorganisation and focal adhesion formation required for directed migration. Differences in the phenotypes generated by knock down of Pak2a and Pak2b may be explained in part by the observation that Pak2a can bind to the adaptor protein Nek while Pak2b cannot. Pak2b is required to establish and/or maintain F-actin organisation, cadherin- mediated adhesion and tissue integrity within the migrating lateral line primordium. We show that dynamic regulation of the actin cytoskeleton and cell adhesion is involved in the formation of rosette-like structures within the lateral line primordium which are deposited as a unit and represent the nascent neuromast precursors. We have also identified possible roles for Pak2a and Pak2b in regulating gene expression in early zebrafish development. Pak2 proteins may control the expression of several genes involved in mesoderm formation through regulation of transcriptional activators and repressors.

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