Feline Lindhout

General discussion 153 5 functioning and axon development might be at play (Zmuda and Rivas 1998; de Anda et al. 2005). However, depleting centrosomes in young polarized neurons did not affect further outgrowth of the yet formed axon, which supported the idea that centrosomes were not important for axon development (Stiess et al. 2010). These contradicting findings are likely explained by the different functions displayed by centrosomes throughout neurodevelopment, as centrosomes gradually lose their microtubule-organizing ability during the process of ciliogenesis (Stiess et al. 2010; Ishikawa and Marshall 2011). Importantly, this developmental process coincides with the time window in which axon outgrowth occurs (Stiess et al. 2010). Accordingly, microtubule-organizing functions of centrosomes are indispensable for neurodevelopmental processes prior to axon outgrowth, such as neurogenesis and the onset of axon formation (Tsai and Gleeson 2005; Lancaster et al. 2013; Nano and Basto 2017; Meka, Scharrenberg, and Calderon de Anda 2020; Stiess et al. 2010) ( Chapter 3 ). These processes critically rely on extensive microtubule remodeling, as this supports the drastic morphological changes of the developing axon and establishes the different microtubule organization in axons and dendrites important for polarized cargo transport (van Beuningen and Hoogenraad 2016). The importance of centrosome function during these early neurodevelopmental processes is further illustrated by a wide range of neurodevelopmental disorders, including microcephaly, that are caused by mutations in centrosome proteins (Nano and Basto 2017). At later developmental stages, when the microtubule organization in axons and dendrites is established, the microtubule- organizing functions of centrosomes become perhaps excessive, as indicated by declining MTOC functions of centrosomes after axon formation. It remains an open question whether the coincident formation of the axon and gradual loss of microtubule-organizing centrosome functions are also mechanistically linked. To this end, new insights may come from studying proteins that show a developmental translocation from centrosomes to axonal microtubules during early axon development. This re-localization process is observed for NDEL proteins in a previous study and Trim46 proteins in Chapter 3 , and future studies may identify more candidates following this developmental transition (Kuijpers et al. 2016). The observed relocation of Trim46 and NDEL possibly hints for a common underlying mechanism linking centrosome function and axon development, although the precise function and mechanistic details remain elusive. Speculatively, the translocation of these proteins assists in axon specification, the first step in axon development that marks the important developmental switch from stage 2 to stage 3 neurons. This process of axon specification critically relies on extensive remodeling of the local microtubule network, and perhaps the presence of microtubule-associated proteins such as Trim46 and NDEL at future axons mediates this process. As such, the translocation of microtubule-organizing proteins from centrosomes to the specified axon could thereby guide the neuron through the subsequent developmental stage. It remains unknown how the translocation of these proteins from centrosomes to axons is controlled. Considering that centrosomes are important sites for the recruitment of diverse signaling molecules, it