Zebrafish Mib Promotes Long-Distance Transport of Jagged2 Via Extracellular Vesicles

Neural progenitors of the ventral spinal cord differentiate into GABAergic Kolmer-Agduhr neurons (KA) under the control of Jagged2-meditated Notch signaling during late neurogenesis. Mib-mediated Notch signaling has also been demonstrated to regulate the number of KA neurons in the p3 domain. However, the relationship between Jagged2 and Mib during late neurogenesis remains unclear. Here we investigate how Mib is involved in the regulation of Jagged2 and the long-range Notch signaling. Ubiquitination of Jagged2 by Mib was found to promote its proteasome-dependent degradation in undifferentiated P19 cells, but not in differentiated P19 cells by retinoic acid. Co-IP assay revealed that Mib physically interacts with Jagged2, but not with the intracellular domain itself. Cell transplantation experiments showed that the formation of extracellular vesicles (EVs) containing Jagged2 was promoted by the co-expression of Mib. Our observations suggest that EVs containing Jagged2 and Mib may play a role in the Notch signaling in discrete compartments of the neural tube during the development of the vertebrate nervous system.