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The role of p35/CDK5 in the developing cerebral cortex

Rakic, S; (2005) The role of p35/CDK5 in the developing cerebral cortex. Doctoral thesis , (UCL) University College London. Green open access

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Abstract

This thesis has focussed on the role of cyclin-dependent kinase 5 (Cdk5) and its activator, p35, in controlling the proper formation of the cerebral cortex. First, cortical layer formation in p35 mutants was re-examined. Interestingly, the prenatal layer I (LI) seems wider, more cellular, and without a clear border with the cortical plate (CP) in these animals. Second, interneuron arrangement in p35 and Cdk5 mutants was studied. Molecules, such as neuregulins (NRGs), which can bind to ErbB receptors and potentially signal through the p35/Cdk5 pathway, were also examined. Cortical interneurons express Cdk5, but Cdk5 is not active in developing forebrain in p35 mutants. It appears that migration of cortical interneurons from the ganglionic eminence (GE) is a Cdk5-independent process. However, my results have suggested that: (i) radial inward migration of interneurons, from LI into the CP, might be a Cdk5-dependent mechanism (ii) prenatal cortical interneurons and projection neurons do not communicate directly. Intriguingly, ErbB4 is highly expressed on the surface of migrating cortical interneurons. Two intracellular isoforms of the rat ErbB4 exist, with one having a unique tyrosine residue for binding PI3-kinase. I have shown that, although ErbB4 signalling is necessary for migration of cortical interneurons from the GE, this process could occur through a PI3K-independent mechanism. The hypothesis that the ErbB4 receptor signals via the Cdk5 pathway was also tested. I found that: (i) Roscovitine, a Cdk5 specific inhibitor, impairs the neuronal chemotactic response to NRGlp (ii) Cdk5 phosphorylates ErbB4 threonine (1152) in vitro. Third, splitting of the preplate layer (PPL) in p35 mutants was studied. In these animals the PPL splits incompletely, which results in misplaced subplate neurons and reeler-Uke positioning of thalamocortical axons. In summary, my experiments have provided novel information about some signalling molecules, and their receptors, that are involved in the migration of cortical neurons.

Type: Thesis (Doctoral)
Title: The role of p35/CDK5 in the developing cerebral cortex
Identifier: PQ ETD:593134
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
URI: http://discovery.ucl.ac.uk/id/eprint/1445810
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