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The E3 Ligase Mind Bomb-1 (Mib1) Modulates Delta-Notch Signaling to Control Neurogenesis and Gliogenesis in the Developing Spinal Cord*

Kyungjoon Kang,Donghoon Lee,Seulgi Hong,Sung-Gyoo Park,Mi-Ryoung Song

Published 2012 in Journal of Biological Chemistry

ABSTRACT

Background: Mib1 is a ubiquitin ligase that modifies Delta, a ligand for the Notch signaling pathway. Results: Absence of Mib1 results in a reduced number of neural progenitors, spinal interneurons, and astrocytes. Conclusion: Mib1 controls neurogenesis and gliogenesis in the spinal cord. Significance: Novel insights about the role of Mind bomb1 in the regulation of early spinal cord development via Delta signaling are presented. The Notch signaling pathway is essential for neuronal and glial specification during CNS development. Mind bomb-1 (Mib1) is an E3 ubiquitin ligase that ubiquitinates and promotes the endocytosis of Notch ligands. Although Mib1 is essential for transmitting the Notch signal, it is still unclear whether it is a primary regulator of Notch ligand activity in the developing spinal cord. In Mib1 conditional knock-out mice, we observed depletion of spinal progenitors, premature differentiation of neurons, and unbalanced specification of V2 interneurons, all of which mimic the conventional Notch phenotype. In agreement with this, the reduction of progenitors in the absence of Mib1 led to a loss of both astrocytes and oligodendrocytes. Late removal of Mib1 using a drug-inducible system suppressed glial differentiation, suggesting that Mib1 continues to play a role in the formation of late progenitors mainly designated for gliogenesis. Finally, misexpression of Mib1 or Mib1 deletion mutants revealed that the ring domain of Mib1 is required for the specification of V2 interneurons in the chick neural tube. Together, these findings suggest that Mib1 is a major component of the signal-sending cells required to provide Notch ligand activity for specifying neurons and glia in the spinal cord.

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