Ephrin-B1 Controls the Columnar Distribution of Cortical Pyramidal Neurons by Restricting Their Tangential Migration

Abstract

Neurons of the cerebral cortex are organized in layers and columns. Unlike laminar patterning, the mechanisms underlying columnar organization remain largely unexplored. Here, we show that ephrin-B1 plays a key role in this process through the control of nonradial steps of migration of pyramidal neurons. In vivo gain of function of ephrin-B1 resulted in a reduction of tangential motility of pyramidal neurons, leading to abnormal neuronal clustering. Conversely, following genetic disruption of ephrin-B1, cortical neurons displayed a wider lateral dispersion, resulting in enlarged ontogenic columns. Dynamic analyses revealed that ephrin-B1 controls the lateral spread of pyramidal neurons by limiting neurite extension and tangential migration during the multipolar phase. Furthermore, we identified P-Rex1, a guanine-exchange factor for Rac3, as a downstream ephrin-B1 effector required to control migration during the multipolar phase. Our results demonstrate that ephrin-B1 inhibits nonradial migration of pyramidal neurons, thereby controlling the pattern of cortical columns.

Wnt Signaling Regulates Multipolar-to-Bipolar Transition of Migrating Neurons in the Cerebral Cortex

“…Ephrin-mediated contact repulsion is critical for the generation and maintenance of cell segregation into domains during development (Wilkinson, 2001), and it has also been implicated in regressive events including axonal and dendritic spine pruning and neuronal death (Vanderhaeghen and Cheng, 2010). Interestingly, members of both class A and B ephrins appear to play an important role in regulating lateral dispersion of pyramidal precursors during the multipolar stage (Torii et al, 2009;Dimidschstein et al, 2013). In particular, ephrin-B1 reverse signaling was shown to activate Rac3 through the P-Rex1 guanylate exchange factor and to reduce neurite dynamics, thereby restricting tangential migration of pyramidal precursors (Dimidschstein et al, 2013).…”

“…Interestingly, members of both class A and B ephrins appear to play an important role in regulating lateral dispersion of pyramidal precursors during the multipolar stage (Torii et al, 2009;Dimidschstein et al, 2013). In particular, ephrin-B1 reverse signaling was shown to activate Rac3 through the P-Rex1 guanylate exchange factor and to reduce neurite dynamics, thereby restricting tangential migration of pyramidal precursors (Dimidschstein et al, 2013). On the other hand, ephrin-B1 loss of function resulted in increased lateral dispersion of cells, most likely as a consequence of increased neurite dynamics and exploratory behavior (Dimidschstein et al, 2013;Torii et al, 2009).…”

“…The guidance molecule ephrin-B1 is expressed in a graded manner in the developing cortex and has been shown to play a critical role in regulating process dynamics and tangential spreading of pyramidal precursors during the multipolar phase (Dimidschstein et al, 2013). It has also been demonstrated that ephrin-B1 expression is inversely regulated by the genetic program driven by Wnt/b-catenin/TCF-4 in colorectal cancer cells (Batlle et al, 2002).…”

Distinct temporal hierarchies in membrane and cytoskeleton dynamics precede the morphological polarization of developing neurons

“…However, non cell-autonomous cues can impinge on those endogenous pathways and thus polarity establishment is a dynamic intrinsic-extrinsic process, where gradients of secreted molecules (e.g. reelin or Semaphorin 3A), extracellular matrix or cell-cell interactions influence neuronal positioning and axondendrite orientation, both in vivo and in vitro (Dimidschstein et al, 2013;Esch et al, 1999;Esch et al, 2000;Gärtner et al, 2012;Jossin and Cooper, 2011;Polleux et al, 1998;Polleux et al, 2000;Tissir and Goffinet, 2003).…”

Rho GTPase isoforms in cell motility: Don't fret, we have FRET

“…99 In contrast, Rac3 and Rac1 appear to perform synergistic roles in the development of the nervous system as loss of both isoforms results in defects in the migration and differentiation of a number of brain cell types. [100][101][102][103] Loss of either isoform in the brain does not lead to obvious defects. 100 These results highlight that each of the Rac isoforms had been specialized for a very particular function and displays its own specific biology.…”