Feline Lindhout

1 General introduction 11 Many studies using in vitro model systems greatly complemented our understanding of neurodevelopment, and particularly provided important insights in the underlying cell-intrinsic and molecular processes. Early studies in dissociated hippocampal and cortical rodent neurons in culture reported that newborn neurons proceed through five neurodevelopmental stages (Fig 1) (Dotti, Sullivan, and Banker 1988; Powell et al. 1997). In stage 1, neurons appear as round symmetric cells with dynamic lamellipodia and filopodia structures. In stage 2, neurons grow multiple processes of similar lengths containing dynamic growth cones. In stage 3 neurons, a symmetry break occurs as one of these processes shows extensive growth compared to the others, and will develop into an axon. Multiple studies showed that Figure 1. Neurodevelopment and centrosome functions A. Schematic overview of the five neurodevelopmental stages. Symmetric neurons with lamellipodia (stage 1) grow multiple non-polarized neurites (stage 2). A single neurite undergoes extensive growth (stage 3), the future axon, whereas the remaining neurites develop intro dendrites (stage 4). Next, neurons undergo synaptogenesis and further mature (stage 5). B. Centrosomes display different functions throughout neurodevelopment. Initially, centrosomes are important microtubule-organizing centers (MTOCs) (stage 1 and 2), and this function is declined as centrosomes transform into cilia during ciliogenesis (stage 4 and 5). This developmental transition occurs in stage 3 neurons, but the exact timing in relation to the process of axon formation is unknown. C. Indication of the developmental timing from neurogenesis (stage 1) to mature neurons (stage 5) in rodents and humans. Data is based on transplanted human and mouse induced pluripotent stem cells (iPSC)-derived neurons in mouse brains (Espuny-Camacho et al. 2013; Maroof et al. 2013; Nicholas et al. 2013; Linaro et al. 2019).