Cadherin-based adhesions in the apical endfoot are required for active Notch signaling to control neurogenesis in vertebrates

Abstract

The development of the vertebrate brain requires an exquisite balance between proliferation and differentiation of neural progenitors. Notch signaling plays a pivotal role in regulating this balance, yet the interaction between signaling and receiving cells remains poorly understood. We have found that numerous nascent neurons and/or intermediate neurogenic progenitors expressing the ligand of Notch retain apical endfeet transiently at the ventricular lumen that form adherens junctions (AJs) with the endfeet of progenitors. Forced detachment of the apical endfeet of those differentiating cells by disrupting AJs resulted in precocious neurogenesis that was preceded by the downregulation of Notch signaling. Both Notch1 and its ligand Dll1 are distributed around AJs in the apical endfeet, and these proteins physically interact with ZO-1, a constituent of the AJ. Furthermore, live imaging of a fluorescently tagged Notch1 demonstrated its trafficking from the apical endfoot to the nucleus upon cleavage. Our results identified the apical endfoot as the central site of active Notch signaling to securely prohibit inappropriate differentiation of neural progenitors.

N-cadherin-based adherens junction regulates the maintenance, proliferation, and differentiation of neural progenitor cells during development

“…44,46 The down-regulation of Notch signaling is important for the downregulation of N-cadherin and subsequent apical process detachment. 127 As described above, some studies show a functional link between Notch signaling and cadherin-mediated AJ. 128,129 In addition, a crosstalk between Notch and Hh signaling pathway has been reported.…”

“…46,126 After asymmetric neurogenic division, numerous nascent neurons and/or IPs expressing the ligand of Notch retain apical process transiently at the ventricular zone in the developing mouse cerebral cortex. 127 Both Notch1 and its ligand Delta-like 1 (Dll1) are distributed around AJs in the apical process. 127 The nascent neurons and IPs inherited lower level of Delta-Notch signaling components than the cell, which maintains the identity of NPC.…”

“…127 Both Notch1 and its ligand Delta-like 1 (Dll1) are distributed around AJs in the apical process. 127 The nascent neurons and IPs inherited lower level of Delta-Notch signaling components than the cell, which maintains the identity of NPC. 44,46 The down-regulation of Notch signaling is important for the downregulation of N-cadherin and subsequent apical process detachment.…”

Epb41l5 competes with Delta as a substrate for Mib1 to coordinate specification and differentiation of neurons

“…5) or the inhibition of N-cadherin function in an NPC (Zhang et al, 2010: Rousso et al, 2012 promotes its differentiation as a neuron. In this context, disengagement of NPCs from their neighbors is likely to promote their neuronal specification, at least in part, because the reduction of AJCs is expected to impair DeltaNotch interactions at AJCs and make lateral inhibition from adjacent NPCs less effective (Hatakeyama et al, 2014). Conversely, less efficient disassembly of AJs of fate-specified NPCs in epb41l5-deficient embryos could permit persistent lateral inhibition from neighboring cells, which might further delay neuronal differentiation.…”

The Cadherin Superfamily in Neural Circuit Assembly

“…In addition to linking adjacent progenitors, adherens junctions also appear to link nascent neurons with their RGC siblings. Many newborn neurons retain an apical process that maintains contact with the ventricular surface, as well as adherens junctions with neighboring cells, and disassembly of these AJs increases neurogenesis through the misregulation of Notch signaling (Hatakeyama et al 2014). …”