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1.
Cereb Cortex ; 27(2): 1253-1269, 2017 02 01.
Article in English | MEDLINE | ID: mdl-26733533

ABSTRACT

During the development of the mammalian neocortex, the generation of neurons by neural progenitors and their migration to the final position are closely coordinated. The highly polarized radial glial cells (RGCs) serve both as progenitor cells to generate neurons and as support for the migration of these neurons. After their generation, neurons transiently assume a multipolar morphology before they polarize and begin their migration along the RGCs. Here, we show that Rap1 GTPases perform essential functions for cortical organization as master regulators of cell polarity. Conditional deletion of Rap1 GTPases leads to a complete loss of cortical lamination. In RGCs, Rap1 GTPases are required to maintain their polarized organization. In newborn neurons, the loss of Rap1 GTPases prevents the formation of axons and leading processes and thereby interferes with radial migration. Taken together, the loss of RGC and neuronal polarity results in the disruption of cortical organization.


Subject(s)
Cell Polarity/physiology , Neocortex/growth & development , Neurogenesis/physiology , rap1 GTP-Binding Proteins/metabolism , Animals , Cell Movement/physiology , Ependymoglial Cells/physiology , Mice , Neocortex/cytology , Neocortex/enzymology , Neuroglia/cytology , Neurons/cytology , Signal Transduction/physiology
2.
PLoS One ; 11(4): e0154174, 2016.
Article in English | MEDLINE | ID: mdl-27111087

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.


Subject(s)
Gene Expression Regulation, Developmental , Guanine Nucleotide-Releasing Factor 2/genetics , Neocortex/metabolism , Neurogenesis/genetics , Neurons/metabolism , Animals , Cell Polarity , Embryo, Mammalian , Guanine Nucleotide-Releasing Factor 2/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Neocortex/cytology , Neocortex/embryology , Neurons/cytology , Signal Transduction , Time-Lapse Imaging , rap GTP-Binding Proteins/genetics , rap GTP-Binding Proteins/metabolism , rap1 GTP-Binding Proteins/genetics , rap1 GTP-Binding Proteins/metabolism
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