Regulation of Cell Delamination During Cortical Neurodevelopment and Implication for Brain Disorders

Abstract

Cortical development is dependent on key processes that can influence apical progenitor cell division and progeny. Pivotal among such critical cellular processes is the intricate mechanism of cell delamination. This indispensable cell detachment process mainly entails the loss of apical anchorage, and subsequent migration of the mitotic derivatives of the highly polarized apical cortical progenitors. Such apical progenitor derivatives are responsible for the majority of cortical neurogenesis. Many factors, including transcriptional and epigenetic/chromatin regulators, are known to tightly control cell attachment and delamination tendency in the cortical neurepithelium. Activity of these molecular regulators principally coordinate morphogenetic cues to engender remodeling or disassembly of tethering cellular components and external cell adhesion molecules leading to exit of differentiating cells in the ventricular zone. Improper cell delamination is known to frequently impair progenitor cell fate commitment and neuronal migration, which can cause aberrant cortical cell number and organization known to be detrimental to the structure and function of the cerebral cortex. Indeed, some neurodevelopmental abnormalities, including Heterotopia, Schizophrenia, Hydrocephalus, Microcephaly, and Chudley-McCullough syndrome have been associated with cell attachment dysregulation in the developing mammalian cortex. This review sheds light on the concept of cell delamination, mechanistic (transcriptional and epigenetic regulation) nuances involved, and its importance for corticogenesis. Various neurodevelopmental disorders with defective (too much or too little) cell delamination as a notable etiological underpinning are also discussed.

Keywords: cell adhesion; cell polarity; cortical development; delamination; epigenetic regulation; neurepithelium; neurodevelopmental disorders; transcription factors.

FIGURE 1

Schema showing neurodevelopment in the mouse cerebral cortex. Early in cortical development, neuroepithelial cells (NECs) first expand their pool via proliferation and then transform into apical radial glial cells (aRGCs). Together, NECs and aRGCs make the apical progenitors (APs) in the developing cortex. Apical progenitors are anchored at the ventricular surface by apical junctional complexes, and also establish basal connection beyond the marginal zone (MZ) to make them have apicobasal polarity. Apical progenitors can produce limited number of neurons by direct neurogenesis. The neuronal pool is increased by indirect neurogenesis via the generation of neuron-amplifying cells such as intermediate progenitor cells (IPCs) and basal radial glial cells (bRGCs) by aRGCs. Newborn neurons migrate by somal translocation or by locomotion using the slender fibers of aRGCs as guides to exit the ventricular zone/subventricular zone (VZ/SVZ) and through the intermediate zone (IZ) to reach their destination in the cortical plate (CP). In the course of corticogenesis, aRGCs give rise to or transform into glial cells (astrocytes, oligodendrocytes or oligodendrocyte precursor cells [OPCs], ependymal cells).

FIGURE 2

Diagram depicting synopsis of cell delamination in the cortical neurepithelium. A typical radial glial cell (x) is anchored at its endfoot by an apical junction/adherens junction. When the radial glial cell receives signals to undergo differentiative/asymmetric division, its soma is positioned at the ventricular surface. The inheritance or distribution of components of the dividing radial glial cell (y) is a determinant of fate of the progenies. The primary cilium and associated mother centrosome, apical membrane, and adherens junction are distributed among the daughter cells such that the one to maintain the radial glia identity bears the primary cilium and associated basal body, acquires most of the apical membrane, and reestablishes the adherens junction (z). The daughter cell poised to differentiate withdraws from the adherens junction belt via apical constriction or abscission at the ventricular surface as delaminated cell, which could end up as a basal progenitor cell, nascent neuron, or a glial cell/precursor that basally relocates in the cortical wall. aRGC, apical radial glial cell; AJ, adherens junction; BB, basal body; PC, primary cilium; CM, ciliary membrane; A, axoneme; BLM, basolateral membrane; AM, apical membrane; OPC, oligodendrocyte precursor cell; BP, basal progenitor.

FIGURE 3

Illustration of the transcriptional and epigenetic regulation of delamination. (A) The delamination of differentiating cells from apical to basal aspect of the cortical wall is under the control of specific transcriptional and epigenetic programs during cortical development. Neural cells at the verge of differentiating activate or suppress certain molecular factors, which lead to their withdrawal from apical adhesion and subsequent exit from the germinal neurepithelium. (B,C) Indicate a typical epigenetic program capable of altering the transcriptome of apical progenitors or their progenies to affect how they delaminate during cortical development. Under normal condition (B), recruitment of the BAF complex, via binding of its scaffolding subunits BAF155 and BAF170, to Pax6-bound regulatory elements promotes the expression of genes necessary for apical cell adhesion, proper orientation of mitotic spindle, and maintenance of the apicobasal polarity of cortical apical progenitors. Together, these preserve the proliferative nature of cortical neurepithelium. (C) However, to activate cell differentiation in the neurepithelium, BAF155 expression is downregulated or inhibited in neuroepithelial cells. A notable mechanism of BAF155 downregulation is inhibition of its expression by METTL3-mediated activity of RBM15 or by RBM15 upregulation. Lack of BAF155 alters PAX6-mediated BAF complex recruitment/engagement leading to downregulation of the genes involved in cell adhesion, cell division, and cell polarity maintenance. These culminate in cell differentiation, loss of adherens junctions, and increased delamination of apical progenitors or their derivatives. Vertical red arrow pointing upward denote upregulation or overexpressing of RBM15. AJ, adherens junction; AP, apical progenitor; BAF, Brg1/Brm associated factor; METTL3, methyltransferase like 3; RBM15, RNA binding motif protein 15.