N-Cadherin Sustains Motility and Polarity of Future Cortical Interneurons during Tangential Migration

Abstract

In the developing brain, cortical GABAergic interneurons migrate long distances from the medial ganglionic eminence (MGE) in which they are generated, to the cortex in which they settle. MGE cells express the cell adhesion molecule N-cadherin, a homophilic cell-cell adhesion molecule that regulates numerous steps of brain development, from neuroepithelium morphogenesis to synapse formation. N-cadherin is also expressed in embryonic territories crossed by MGE cells during their migration. In this study, we demonstrate that N-cadherin is a key player in the long-distance migration of future cortical interneurons. Using N-cadherin-coated substrate, we show that N-cadherin-dependent adhesion promotes the migration of mouse MGE cells in vitro. Conversely, mouse MGE cells electroporated with a construct interfering with cadherin function show reduced cell motility, leading process instability, and impaired polarization associated with abnormal myosin IIB dynamics. In vivo, the capability of electroporated MGE cells to invade the developing cortical plate is altered. Using genetic ablation of N-cadherin in mouse embryos, we show that N-cadherin-depleted MGEs are severely disorganized. MGE cells hardly exit the disorganized proliferative area. N-cadherin ablation at the postmitotic stage, which does not affect MGE morphogenesis, alters MGE cell motility and directionality. The tangential migration to the cortex of N-cadherin ablated MGE cells is delayed, and their radial migration within the cortical plate is perturbed. Altogether, these results identify N-cadherin as a pivotal adhesion substrate that activates cell motility in future cortical interneurons and maintains cell polarity over their long-distance migration to the developing cortex.

Auditory cortex interneuron development requires cadherins operating hair-cell mechanoelectrical transduction

“…6C) and cdhr15 + neurons migrating from Cdhr23 −/− explants (Kolmogorov-Smirnov test, P = 0.95). These cell polarity deficits of newborn interneurons are consistent with the in vivo misrouting of interneuron precursors (32) in Cdhr23 −/− and Cdhr15 −/− embryos (Fig. 6B).…”

“…This additional role of cdhr15 may reflect the early involvement of this cdhr in GABAergic interneuron synaptogenesis, which is considered to be essential for interneuron survival (42). This dual role is reminiscent of the role reported for two other adhesion proteins in GABAergic interneuron precursors in the embryonic telencephalon: celsr3 (also known as adgrc3) (43) [from the flamingo cadherin (9) and adhesion G protein-coupled receptor families (44)] and cdh2 (32). However, these two proteins are not required for the specific targeting of interneuron precursors to a particular neocortical area.…”

“…For immunofluorescence analyses, the antibodies directed against cdhr23 and cdhr15 were used as described by Pepermans et al (16) and Sahly et al (59). Culture of MGE explants and quantification of neuronal migration were carried out as described by Luccardini et al (32). …”

A crucial role for polysialic acid in developmental interneuron migration and the establishment of interneuron densities in the mouse prefrontal cortex

“…By contrast, ablation of either CXCR4 or CXCR7 chemokine receptor caused increased or reduced interneuron motility with longer or shorter leading processes, respectively (Wang et al, 2011). Of particular interest, perturbation of N-cadherin-mediated cell adhesion produced slower MGE-derived interneurons with shorter and less stable leading processes (Luccardini et al, 2013). Similarly, altered cell adhesion might be the primary mechanism by which polySia affects leading process morphology and interneuron migration.…”

“…Alterations of leading process morphology have been repeatedly linked to migration deficits (Nasrallah et al, 2006;Friocourt et al, 2007;Wang et al, 2011;Steinecke et al, 2012;Luccardini et al, 2013). To study the potential impact of polySia on the morphology of the leading process, coronal slices of E12.5 GAD67-GFP mice were cultured in the presence or absence of endo and the lengths of leading processes were evaluated after 1 day in vitro.…”