Functional analysis of RAC1B during neuronal development

Albertinazzi, Chiara (2003). Functional analysis of RAC1B during neuronal development. PhD thesis The Open University.



Neurite extension requires the concerted action of a number of events including actin polymerization at the growth cone, formation of new adhesive sites to the substrate, and membrane addition, to extend the surface of the elongating neurite. The small GTPase Rac IB, identified from developing chicken retina, is specifically expressed during neural development, and overexpression of Rac IB in embryonic retinal neurons specifically stimulates neurite extension and branching (Albertinazzi et al., 1998). Very little is known about the molecular mechanisms which coordinate Rac IB-mediated neurite extension. In order to study in detail this mechanism in an in vivo system, recombinant embryonic stem cells (ES) for the deletion of mouse Rac IB gene were produced. ES cells from four independent clones that resulted positive for the deletion of mouse Rac IB gene were microinjected in blastocysts, and chimeric mice were generated to be used for the generation of Rac IB-null mice.

Recently, p95-APPl was identified as a protein able to interact with Rac IB in a GTP-dependent manner (Di Cesare et al. 2000). P95-APP1 is an ArfGAP of the GIT family, highly expressed in the developing nervous system. Expression of p95- APPl with a mutated or deleted ArfGAP domain in retinal neurons prevented Rac IB-induced neuritogenesis, leading to PIX-mediated accumulation of mutant p95-APPl and associated proteins at large Rab 11-positive endocytic vesicles. Analysis of neurons expressing different p95-derived constructs together with wild-type or mutant Arf6 GTPases revealed the requirement of both p95-APPl and a cycling Arf6 for a normal Rac IB-mediated neuritogenesis.

The data obtained in this thesis show a functional connection between the localization of the p95-APPl complex at recycling endosomes and Rac IB-dependent neuritogenesis, and suggest a role of this complex in the regulation of membrane recycling to/from the neuronal surface during neuritogenesis.

Viewing alternatives

Download history


Public Attention

Altmetrics from Altmetric

Number of Citations

Citations from Dimensions

Item Actions