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Mib1 prevents Notch Cis-inhibition to defer differentiation and preserve neuroepithelial integrity during neural delamination.

Baek C, Freem L, Goïame R, Sang H, Morin X, Tozer S.

Author summary

The process of neural delamination, whereby nascent neurons detach from the ventricular surface of the neural tube after differentiation, is still poorly characterized. The vertebrate neural tube is initially exclusively composed of neuroepithelial progenitors whose apical attachments ensure the integrity of the ventricular wall. However, as differentiation takes place, increasing numbers of progenitors exit the cell cycle and delaminate, therefore challenging the integrity of the apical surface. Here, we have analyzed the mechanisms underlying the delamination process in the neuroepithelial tissue. We show that the Notch signaling pathway is active in all progenitors and that its repression is critical for prospective neurons to commit to differentiation. Moreover, we find that the Notch ligand Delta-like 1 (Dll1) represses Notch activity through Cis-inhibition of the Notch receptor and induces differentiation. Strikingly, we show that the ubiquitin ligase Mindbomb1 blocks the Cis-inhibition process and allows Notch activity to be transiently sustained, which defers differentiation. This transition period is essential for prospective neurons to constrict their apical domain before delamination, as the alteration of this sequence results in breaches in the ventricular wall, followed by massive tissue disorganization. Taken together, our results reveal that the temporal control of Notch down-regulation needs to be tightly coordinated with the delamination process to preserve the integrity of the ventricular wall while allowing neuroepithelial cells to differentiate.

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PLoS Biol. 2018 Apr 30 ;16(4):e2004162. doi : 10.1371/journal.pbio.2004162.