CRC 629 B14 - Conserved polarity mechanisms in asymmetric cell division, neuronal polarization and neuronal migration

Basic data for this project

Description

Cell polarity is defined as asymmetry in cell shape, protein distributions and cell functions. It is characteristic of single-cell organisms, including yeast and bacteria, and cells in tissues of multi-cell organisms such as worms, flies and mammals (Nelson, 2003). During its lifespan a neuron passes through at least three polarity-dependent processes, in a first step a neuron is born through asymmetric cell division of a neural precursor cell, then this young neuron migrates to its position in the brain and finally the neurites have to be specified to be become axon and dendrites. In mammals so far all proteins that have been shown to be involved in asymmetric cell division in neural progenitor cells show an apical localization during mitosis of these cells (PAR-3, PAR-6, aPKC, Numb). Later in development, during neuronal migration these proteins are localized at the leading edge of the migrating cells while they become involved in axon specification during neuronal polarization. But, as we demonstrated recently the protein TRIM32 is the only so far described protein that shows localization at the basal pole of dividing neural progenitor cells. This raises two interesting questions: Is TRIM32 also involved in neuronal migration and if so is it localized not the leading edge but to the trailing edge? Is TRIM32 also involved in neuronal polarization and if so is it involved in specification of dendritic identity (opposite to the function off all other so fare identified “polarity proteins”)? If TRIM32 is indeed involved in neuronal migration and/or axon specification we want to identify the molecular mechanism that is used by it. TRIM32 and its homolog TRIM2 have been shown to act as an ubiquitin ligase for several targets including c-Myc, Actin and Neurofilament light chain. Furthermore TRIM2 also binds to, but is not ubiquitinating, Myosin Va. It is very well described that local regulation of the stability of the cytoskeleton is involved in the regulation of migration and axon specification. Therefore a model where TRIM32 is localized in a specific subcellular region, like the trailing edge of a migrating cell or the tip of growing dendrites, and there mediates the ubiquitination and degradation of specific compounds of the cytoskeleton (like actin or neurofilaments) seems to be very attractive. Furthermore this specific subcellular localization could be achieved by actively targeted transport via Myosin. Furthermore TRIM32 is able to bind to the RNAse Argonaute-1 and thereby regulates the activity of certain micro-RNAs. Also the regulation of local translation through regulated micro-RNA activity might contribute to the establishment and maintenance of cellular polarity. We hope that understanding how a neuron is born from a neural stem cell, then reaches it`s appropriate position in the brain and finally sends out it`s axon and dendrites to the right targets will allow us to use neural stem cells to replace neurons that are lost in the course of neurodegenerative diseases.