Abstract
The establishment of a polarized morphology is essential for the development and function of neurons. During the development of the mammalian neocortex, neurons arise in the ventricular zone (VZ) from radial glia cells (RGCs) and leave the VZ to generate the cortical plate (CP). During their migration, newborn neurons first assume a multipolar morphology in the subventricular zone (SVZ) and lower intermediate zone (IZ). Subsequently, they undergo a multi-to-bipolar (MTB) transition to become bipolar in the upper IZ by developing a leading process and a trailing axon. The small GTPases Rap1A and Rap1B act as master regulators of neural cell polarity in the developing mouse neocortex. They are required for maintaining the polarity of RGCs and directing the MTB transition of multipolar neurons. Here we show that the Rap1 guanine nucleotide exchange factor (GEF) C3G (encoded by the Rapgef1 gene) is a crucial regulator of the MTB transition in vivo by conditionally inactivating the Rapgef1 gene in the developing mouse cortex at different time points during neuronal development. Inactivation of C3G results in defects in neuronal migration, axon formation and cortical lamination. Live cell imaging shows that C3G is required in cortical neurons for both the specification of an axon and the initiation of radial migration by forming a leading process.
Highlights
The complex structure of the mammalian cortex depends on the precise control of the polarization and migration of neural cells
Single confocal planes are shown. (C) Haematoxylin/ eosin staining of coronal sections from the rostral brain shows defects in cortical lamination in the C3GEmx1-KO cortices beginning at E13 compared to the heterozygous controls (+/-:C3Gflox/+;Emx1cre/+)
Rap1 GTPases are required in multipolar neurons for the MTB transition
Summary
The complex structure of the mammalian cortex depends on the precise control of the polarization and migration of neural cells. The first wave of postmitotic neurons forms the transient preplate (PP) that is split by the following wave of neurons into the marginal zone (MZ) and the subplate (SP) [2] During their migration, newborn neurons first assume a multipolar morphology in the SVZ and lower IZ [3,4,5,6]. Successive divisions generate neurons that migrate past older ones to generate the six layers of the cortex in an inside-out pattern [11]. This process depends on the extracellular matrix protein reelin that is produced by the Cajal-Retzius (CR) cells located in the MZ [12, 13]. Reelin regulates inside-out integrin-mediated adhesion during terminal translocation through C3G and Rap1 [20]
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