SUMMARY Neuronal migration is critical for establishing neocortical cell layers and migration defects can cause neurological and psychiatric diseases. Recent studies show that radially migrating neocortical neurons use glia-dependent and glia-independent modes of migration, but the signaling pathways that control different migration modes and the transitions between them are poorly defined. Here, we show that Dab1, an essential component of the reelin pathway, is required in radially migrating neurons for glia-independent somal translocation, but not for glia-guided locomotion. During migration, Dab1 acts in translocating neurons to stabilize their leading processes in a Rap1-dependent manner. Rap1, in turn, controls cadherin function to regulate somal translocation. Furthermore, cell-autonomous neuronal deficits in somal translocation are sufficient to cause severe neocortical lamination defects. Thus, we define the cellular mechanism of reelin function during radial migration, elucidate the molecular pathway downstream of Dab1 during somal translocation, and establish the importance of glia-independent motility in neocortical development.

During development of the mammalian cerebral cortex, radial glial cells (RGCs) generate layer-specific subtypes of excitatory neurons in a defined temporal sequence, in which lower layer neurons are formed before upper layer neurons. It has been proposed that neuronal subtype fate is determined by birthdate via progressive restriction of the neurogenic potential of a common RGC progenitor. We now demonstrate that the murine cerebral cortex contains RGC sublineages with distinct fate potentials. Using in vivo genetic fate mapping and in vitro clonal analysis, we identify an RGC lineage that is intrinsically specified to generate only upper layer neurons, independently of niche and birthdate. Since upper cortical layers were expanded during primate evolution, amplification of this RGC pool may have facilitated human brain evolution.

Cajal-Retzius (CR) cells are a transient cell population of the CNS that is critical for brain development. In the neocortex, CR cells secrete reelin to instruct the radial migration of projection neurons. It has remained unexplored, however, whether CR cells provide additional molecular cues important for brain development. Here, we show that CR cells express the immunoglobulin-like adhesion molecule nectin1, whereas neocortical projection neurons express its preferred binding partner, nectin3. We demonstrate that nectin1/3-mediated interactions between CR cells and the leading processes of migrating neurons are critical for radial migration. Furthermore, reelin signaling to Rap1 promotes Cdh2 function in neurons via nectin3 and afadin, thus directing the broadly expressed homophilic cell adhesion molecule Cdh2 towards mediating heterotypic cell-cell interactions between neurons and CR cells. Our findings identify nectins/afadin as components of the reelin signaling pathway and demonstrate that coincidence signaling between CR cell-derived secreted and short-range guidance-cues direct neuronal migration.

Centrosomes are the major microtubule nucleating center in the cell; they also contribute to spindle pole organization and play a role in cell cycle progression as well as completing cytokinesis. Here we describe the molecular characterization of a novel human gene, CEP55, located in 10q23.33 that is expressed in multiple tissues and various cancer cell lines. Sequence analysis of the cDNA predicted a protein of 464 amino acids with several putative coiled-coil domains that are responsible for protein-protein interactions. Indeed, we found homodimerization of CEP55 by coimmunoprecipitation. Subcellular localization analysis revealed that endogenous CEP55 as well as an EGFP-CEP55 fusion protein is present at the centrosome throughout mitosis, whereas it also appears at the cleavage furrow in late anaphase and in the midbody in cytokinesis. Neither nocodazole nor taxol interfered with centrosome association of endogenous CEP55, suggesting that it directly interacts with centrosome components rather than with microtubules. In microtubule regrowth assays, overexpression of CEP55 did not enhance or inhibit microtubule nucleation. Together, these data suggest a possible involvement of CEP55 in centrosome-dependent cellular functions, such as centrosome duplication and/or cell cycle progression, or in the regulation of cytokinesis.