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Development. 2016 Sep 1;143(17):3085-96. doi: 10.1242/dev.138743. Epub 2016 Aug 10.

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

Author information

1
Department of Cell Biology and Molecular Medicine, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, NJ 07103, USA Section on Neural Developmental Dynamics, Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA matsudmi@njms.rutgers.edu chitnisa@mail.nih.gov.
2
Section on Neural Developmental Dynamics, Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
3
Department of Cell Biology and Molecular Medicine, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, NJ 07103, USA.
4
Section on Neural Developmental Dynamics, Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA Department of Pharmacology, Chiba University, Chiba 260-8675, Japan.
5
Section on Neural Developmental Dynamics, Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA matsudmi@njms.rutgers.edu chitnisa@mail.nih.gov.

Abstract

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.

KEYWORDS:

Epb41l5; Epithelial morphogenesis; Mind bomb; Neurogenesis; Neuronal differentiation; Notch signaling; Zebrafish

PMID:
27510968
PMCID:
PMC5047669
DOI:
10.1242/dev.138743
[Indexed for MEDLINE]
Free PMC Article

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