Feline Lindhout

1 10 The human brain is populated by ~10 11 neurons that are highly interconnected to form complex neuronal networks (Azevedo et al. 2009; von Bartheld, Bahney, and Herculano- Houzel 2016). Neurons are compartmentalized into two morphologically, structurally and functionally distinct domains: the axonal and the somatodendritic domain. These different compartments give rise to intracellular polarity within neurons, thereby enabling the directional flow of information processing in neuronal networks. The axonal domain is a single process originating from the soma, and is characterized by its excessive length and narrow width. This extreme axon morphology is accompanied by large adaptations of axonal substructures, which play important roles in axon functioning. A key function of axons is facilitating firing of action potentials, electrical excitation waves generated at the beginnings of axons and further propagated along axonal membranes. The somatodendritic domain, comprised of the soma and multiple dendritic processes, receives and integrates input coming from axons of other neurons. In neuronal networks, information transmission occurs at highly specialized synaptic connections between the axon and the somatodendritic domains of different neurons. Synapses are subdivided into distinct specialized subdomains, thereby displaying that polarity is also observed at the synaptic level. Specifically, synapses contain a presynaptic site located on axons, a postsynaptic site located on dendrites, and a narrow synaptic cleft in between. In conclusion, axon formation and functioning are key for establishing and maintaining neuronal polarity, which is fundamental for information processing in neuronal networks. This thesis aims to identify and dissect new molecular processes that are important for axon formation and functioning. This chapter covers a broad and general introduction of the key topics presented in this thesis, and specific research questions are further laid out in their corresponding chapters (Chapter 2, 3 and 4). Neurodevelopment Developing neurons: insights from rodents Important advances in understanding mammalian brain development come from a large body of work using rodent model systems. The development of the vertebrate brain begins with the folding and closing of a pseudostratified epithelial sheet, the neuroepithelium, thereby forming the neural tube (Kelava and Lancaster 2016). The neural tube, composed of neuroepithelial cells, undergoes lateral expansion to later generate various structures in the central nervous system. After the lateral expansion of the neural tube, the neuroepithelial cells transform into self-renewing radial glia cells (RGCs), which leads to the thickening of the neuronal tissue and thereby giving rise to the ventricular zone (VZ) (Bystron, Blakemore, and Rakic 2008). Asymmetric divisions of RGCs result in either newborn neurons or in intermediate progenitors (IPs), which populate the subventricular zone (SVZ) and later differentiate into neurons. The immature neurons migrate towards their target location, in a process known as neuronal delamination (Evsyukova, Plestant, and Anton 2013; Theveneau and Mayor 2012). As such, the six layers of the cerebral cortex are formed following an inside-out fashion, in which early-born neurons first form deeper layers followed by the formation of the more superficial layers. In developing brains, the process of neuronal migration highly coincides with axon formation and pathfinding of neurons (Noctor et al. 2004).