Adherens Junctions: Guardians of Cortical Development

Abstract

Apical radial glia comprise the pseudostratified neuroepithelium lining the embryonic lateral ventricles and give rise to the extensive repertoire of pyramidal neuronal subtypes of the neocortex. The establishment of a highly apicobasally polarized radial glial morphology is a mandatory prerequisite for cortical development as it governs neurogenesis, neural migration and the integrity of the ventricular wall. As in all epithelia, cadherin-based adherens junctions (AJs) play an obligate role in the maintenance of radial glial apicobasal polarity and neuroepithelial cohesion. In addition, the assembly of resilient AJs is critical to the integrity of the neuroepithelium which must resist the tensile forces arising from increasing CSF volume and other mechanical stresses associated with the expansion of the ventricles in the embryo and neonate. Junctional instability leads to the collapse of radial glial morphology, disruption of the ventricular surface and cortical lamination defects due to failed neuronal migration. The fidelity of cortical development is therefore dependent on AJ assembly and stability. Mutations in genes known to control radial glial junction formation are causative for a subset of inherited cortical malformations (neuronal heterotopias) as well as perinatal hydrocephalus, reinforcing the concept that radial glial junctions are pivotal determinants of successful corticogenesis. In this review we explore the key animal studies that have revealed important insights into the role of AJs in maintaining apical radial glial morphology and function, and as such, have provided a deeper understanding of the aberrant molecular and cellular processes contributing to debilitating cortical malformations. We highlight the reciprocal interactions between AJs and the epithelial polarity complexes that impose radial glial apicobasal polarity. We also discuss the critical molecular networks promoting AJ assembly in apical radial glia and emphasize the role of the actin cytoskeleton in the stabilization of cadherin adhesion -a crucial factor in buffering the mechanical forces exerted as a consequence of cortical expansion.

Differential Spatiotemporal Expression of Type I and Type II Cadherins Associated With the Segmentation of the Central Nervous System and Formation of Brain Nuclei in the Developing Mouse

“…Cadherin-mediated adherens junction formed between radial glial cells are also necessary for generating and maintaining cell polarity required for the histological organization of the cerebral cortex (Hatakeyama et al, 2014;Veeraval et al, 2020).…”

“…Indeed, several classical cadherins are expressed in a variety of synapses and contribute to pre and postsynaptic differentiation ( Huntley and Benson, 1999 ; Rubio et al, 2005 ; Takeichi, 2007 ; Bekirov et al, 2008 ; Williams et al, 2011 ; Flannery and Brusés, 2012 ; Kuwako et al, 2014 ; Sanes and Zipursky, 2020 ). Cadherin-mediated adherens junction formed between radial glial cells are also necessary for generating and maintaining cell polarity required for the histological organization of the cerebral cortex ( Hatakeyama et al, 2014 ; Veeraval et al, 2020 ).…”

Developmental malformations in Huntington disease: neuropathologic evidence of focal neuronal migration defects in a subset of adult brains

“…Such junctions are crucial for apicobasal polarity within the neuroepithelium and for cellular cohesion. If perturbed, this could affect neuronal migration and also lead to heterotopia formation [ 21 , 36 , 56 , 61 ].…”

Extracellular Control of Radial Glia Proliferation and Scaffolding During Cortical Development and Pathology

“…Therefore, this complex links the actin cytoskeleton to the plasma membrane to form cadherin mediated cell-cell adhesion sites (Drees et al, 2005;Nelson, 2008;Pokutta et al, 2008;Benjamin et al, 2010;Maiden and Hardin, 2011). Many studies (Miyamoto et al, 2015;Veeraval et al, 2020) emphasize the fact that N-cadherin based AJs are key elements for the development of cortical architecture. Several proteins involved in the maintenance of AJs, including afadin, as well as N-cadherin, αE catenin, β catenin, are essential for the formation and maintenance of the RG scaffold (Table 1).…”