Stick around: Cell-Cell Adhesion Molecules during Neocortical Development

Abstract

The neocortex is an exquisitely organized structure achieved through complex cellular processes from the generation of neural cells to their integration into cortical circuits after complex migration processes. During this long journey, neural cells need to establish and release adhesive interactions through cell surface receptors known as cell adhesion molecules (CAMs). Several types of CAMs have been described regulating different aspects of neurodevelopment. Whereas some of them mediate interactions with the extracellular matrix, others allow contact with additional cells. In this review, we will focus on the role of two important families of cell-cell adhesion molecules (C-CAMs), classical cadherins and nectins, as well as in their effectors, in the control of fundamental processes related with corticogenesis, with special attention in the cooperative actions among the two families of C-CAMs.

Keywords: CAMs; axon targeting; classical cadherins; nectins; neocortical development; neurodevelopmental disorders; neuronal migration; neurons; radial glia cells; synaptogenesis.

Figure 1

Classification of classical cadherins, nectins, Necls, and their principal binding partners. (A) Structural representation of type I/II classical cadherins. These cadherins contain an extracellular region to mediate adhesive interactions, a transmembrane domain, and a cytoplasmic tail with several binding domains to catenin proteins. (B) structural representation of catenin proteins. α-catenin can bind cadherins to the actin cytoskeleton through β-catenin. P120-catenin present a cadherin binding domain. (C) structural representation of nectin and Necl families. These Ig-CAMs contain three extracellular Ig-like loops necessary to establish adhesive contacts, a transmembrane region and a cytoplasmic region allowing the interaction with several binding partners including afadin. (D) structural representation of afadin displaying its multiple binding domains. Abbreviations: 4.1BM, 4.1 binding motif; actin-BD, actin-binding domain; AR, Armadillo repeats; C2, C2-type domain; CBD, catenin-binding domain; CT, C-terminal; DD, dimerization domain; DIL, dilute domain; EC, Ectodomain; FHA, forkhead-associated domain; JMD, juxtamembrane domain; MD, M-domain; NT, N-terminal; PDZ, PDZ domain; PR, proline-rich domain; TM, transmembrane domain; V, V-Type; RA, Ras-associate domain.

Figure 2

C-CAMs implication in control of proliferation during neocortical development. (A) schematic representation of the normal neocortex development. Radial glial cells (RGCs) mostly divide asymmetrically to self-renew and produce a postmitotic neuron or an intermediate progenitor cell (not shown). (B) perturbation of AJ-associated genes such as afadin and Cdh2 causes increased proliferation, cortical hyperplasia, double cortex formation, and enlarged production of Cux1+ neurons. (C) disruption of other junctional proteins like β-catenin and Pals-1 disassembles AJs causing a decrease in proliferation and leading to a reduced neocortical structure. EWM, ectopic white matter; HC, Heterotopic Cortex; NC, Normocortex; WM, white matter.

Figure 3

C-CAMs involvement in radial migration during neocortical development. (A) radial migration modes used by cortical projection neurons at early and late embryonic ages. (B) reelin signaling pathway enhances cell–cell adhesion between Cajal–Retzius cells and migrating neurons via nectin1/3 trans-interaction and Cdh2 recruitment in a Dab1/Rap1-depending way. (C) schematics of cadherin vesicle trafficking and nucleokinesis during glia-guided locomotion. (C′) Rab5 and Rab11 respectively participate in endocytosis recycling vesicles carrying Cdh2. (C″) PTP1B cooperates with α/β-catenins connecting Cdh2/4 to the actin cytoskeleton. Abbreviations: CP, cortical plate; CR, Cajal–Retzius; MZ, marginal zone; RGC, radial glial cells; SVZ, subventricular zone; VZ, ventricular zone.

Figure 4

C-CAMs roles in axonal outgrowth, target recognition, and synaptogenesis. (A). schematics of axonal pathfinding in the neocortex showing the generation of callosal projections. From left to right: upon polarization postmitotic neurons start extending their axon through the intermediate zone and across the corpus callosum until reaching matching targets (dark blue cells) in the contralateral hemisphere. Different colors represent possible adhesion codes generated by particular expression of C-CAMs. (B) schematic representation of the temporal progression of synaptogenesis upon target recognition of the axon. In this example synapse formation begins with interaction of nectins between the axon and philopodia-prottuding dendrites (1), followed by cadherin recruitment to the nascent presynaptic and postsynaptic zones (2), and the progressive assembly of the active zone (AZ) and postsynaptic densities (PSD) to stabilize the synaptic contact, in this case with the formation of a dendritic spine (3).