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


The vertebrate neuroepithelium is composed of elongated progenitors whose reciprocal attachments ensure the continuity of the ventricular wall. As progenitors commit to differentiation, they translocate their nucleus basally and eventually withdraw their apical endfoot from the ventricular surface. However, the mechanisms allowing this delamination process to take place while preserving the integrity of the neuroepithelial tissue are still unclear. Here, we show that Notch signaling, which is classically associated with an undifferentiated state, remains active in prospective neurons until they delaminate. During this transition period, prospective neurons rapidly reduce their apical surface and only later down-regulate N-Cadherin levels. Upon Notch blockade, nascent neurons disassemble their junctions but fail to reduce their apical surface. This disrupted sequence weakens the junctional network and eventually leads to breaches in the ventricular wall. We also provide evidence that the Notch ligand Delta-like 1 (Dll1) promotes differentiation by reducing Notch signaling through a Cis-inhibition mechanism. However, during the delamination process, the ubiquitin ligase Mindbomb1 (Mib1) transiently blocks this Cis-inhibition and sustains Notch activity to defer differentiation. We propose that the fine-tuned balance between Notch Trans-activation and Cis-inhibition allows neuroepithelial cells to seamlessly delaminate from the ventricular wall as they commit to differentiation.

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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