Journal
PLOS BIOLOGY
Volume 16, Issue 4, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pbio.2004162
Keywords
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Categories
Funding
- INSERM Avenir [R08221JS]
- Fondation pour la Recherche Medicale (FRM) [DEQ20150331735]
- Fondation ARC [RAC12013]
- Agence Nationale pour la Recherche (ANR) [ANR-12-BSV2-0014-01]
- AFM Thelethon [R16078JJ]
- Canceropele Ile-de-France [2013-2-INV-05]
- Federation pour la recherche sur le Cerveau (FRC) [AOE-9 2014]
- ANR [ANR-10-LABX-54 MEMO LIFE, ANR-11-IDEX-0001-02 PSL]
- Neuropole de Recherche Francilien
- Institut National du Cancer (INCa) [R10074JJ]
- Ministere de lEnseignement superieur et de la Recherche (MESR)
- Wellcome Trust [WT094182AIA]
- BBSRC
- BBSRC [BBS/E/D/20221658, BBS/E/D/10002071, BBS/E/D/20320000] Funding Source: UKRI
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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.
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