Regulation of neocortical development by the E3 ubiquitin ligase IDOL

• Applicant: Dr. Christopher Patzke
• Subject Area: Developmental Neurobiology
• Term: from 2011 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 209741245

The development of the mammalian neocortex is critically dependent on the migration of neurons from their place of birth into the cortical wall. Excitatory neurons that are born in the ventricular zone invade the developing cortical wall by radial migration routes while inhibitory neurons migrate on tangential routes to their target areas. In contrast to the classical view, recent findings show that not all radially migrating neurons are guided by radial glial fibers. Some neurons migrate independent of the glial scaffold or switch between glia-independent and -dependent modes of migration. A recent study has shown that the extracellular matrix glycoprotein reelin is critical for glia-independent radial migration by binding to its receptors ApoER2 or VLDLR on migrating neurons, triggering phosphorylation of the effector protein Dab1, followed by activation of the small GTPase Rap1, which in turn regulates cadherin function. However, one major unresolved question is how the responsiveness of neurons to reelin is controlled. Are neurons receptive to reelin signaling only during distinct phases of migration? And how is the response to reelin terminated? Intriguingly, studies that were carried out in non-neuronal tissue demonstrate that ApoER2 and VLDLR are targets for degradation mediated by the E3 ubiquitin ligase IDOL. Here, I hypothesize that IDOL-mediated ubiquitination and protein degradation function as a feedback mechanism to control the neuronal response to reelin. To test this hypothesis I will use in utero electroporation of RNA interference constructs and genetically modified mice to determine to which extent IDOL mediates reelin-dependent neuronal migration. I will also use proteomics approaches to define the spectrum of neuronal proteins whose ubiquitination depends on IDOL. I anticipate that these findings will lead to important insights into the function of ubiquitination in reelin signaling and neocortical development.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Ulrich Mueller