We identified Erythrocyte membrane protein band 4.1-like 5 (Epb41l5) as a substrate for the E3 ubiquitin ligase Mind bomb 1 (Mib1), which is essential for activation of Notch signaling. Although loss of Epb41l5 does not significantly alter the pattern of neural progenitor cells (NPCs) specified as neurons at the neural plate stage, it delays their delamination and differentiation after neurulation when NPCs normally acquire organized apical junctional complexes (AJCs) in the zebrafish hindbrain. Delays in differentiation are reduced by knocking down N-cadherin, a manipulation expected to help destabilize adherens junctions (AJs). This suggested that delays in neuronal differentiation in epb41l5-deficient embryos are related to a previously described role for Epb41l5 in facilitating disassembly of cadherin-dependent AJCs. Mib1 ubiquitylates Epb41l5 to promote its degradation. DeltaD can compete with Epb41l5 to reduce Mib1-dependent Epb41l5 degradation. In this context, increasing the number of NPCs specified to become neurons, i.e. cells expressing high levels of DeltaD, stabilizes Epb41l5 in the embryo. Together, these observations suggest that relatively high levels of Delta stabilize Epb41l5 in NPCs specified as neurons. This, we suggest, helps coordinate NPC specification with Epb41l5-dependent delamination and differentiation as neurons.
The authors declare no competing or financial interests.
Conceptualization: M.M., A.B.C.; Methodology: M.M., A.B.C.; Formal analysis: M.M.; Investigation: M.M., K.R., G.P., N.S., H.I., D.D.N., M.I.; Writing – original draft preparation: M.M.; Writing – review and editing: M.M., D.D.N., A.B.C.; Funding acquisition: M.M., A.B.C.
This research was supported by the National Institute of Child Health and Human Development (NICHD, NIH) [HD062561 to M.M] and NICHD intramural program [HD001012 to A.B.C.]. Deposited in PMC for release after 12 months.
Supplementary information available online at http://dev.biologists.org/lookup/doi/10.1242/dev.138743.supplemental
- Received May 3, 2016.
- Accepted July 26, 2016.