Nodal proteins, members of the transforming growth factor–β (TGFβ) superfamily, have been identified as key endogenous mesoderm inducers in vertebrates. Precise control of Nodal signaling is essential for normal development of embryos. Here, we report that zebrafish dapper2 ( dpr2 ) is expressed in mesoderm precursors during early embryogenesis and is positively regulated by Nodal signals. In vivo functional studies in zebrafish suggest that Dpr2 suppresses mesoderm induction activities of Nodal signaling. Dpr2 is localized in late endosomes, binds to the TGFβ receptors ALK5 and ALK4, and accelerates lysosomal degradation of these receptors.

Regeneration is an evolutionarily conserved process in animal kingdoms, however, the regenerative capacities differ from species and organ/tissues. Mammals possess very limited regenerative potential to replace damaged organs, whereas non-mammalian species usually have impressive abilities to regenerate organs. The regeneration process requires proper spatiotemporal regulation from key signaling pathways. The canonical Notch and Wnt signaling pathways, two fundamental signals guiding animal development, have been demonstrated to play significant roles in the regeneration of vertebrates. In recent years, increasing evidence has implicated the cross-talking between Notch and Wnt signals during organ regeneration. In this review, we summarize the roles of Notch signaling and Wnt signaling during several representative organ regenerative events, emphasizing the functions and molecular bases of their interplay in these processes, shedding light on utilizing these two signaling pathways to enhance regeneration in mammals and design legitimate therapeutic strategies.

It takes two kinases and two phosphatases acting on a single membrane protein Smoothened to interpret the Hedgehog morphogen gradient.

Notch signaling is highly conserved in all metazoan animals and plays critical roles in cell fate specification, cell proliferation, apoptosis, and stem cell maintenance. Although core components of the Notch signaling cascade have been identified, many gaps in the understanding of the Notch signaling pathway remain to be filled. One form of posttranslational regulation, which is controlled by the ubiquitin-proteasome system, is known to modulate Notch signaling. The ubiquitination pathway is a highly coordinated process in which the ubiquitin moiety is either conjugated to or removed from target proteins by opposing E3 ubiquitin ligases and deubiquitinases (DUBs). Several E3 ubiquitin ligases have been implicated in ubiquitin conjugation to the receptors and the ligands of the Notch signaling cascade. In contrast, little is known about a direct role of DUBs in Notch signaling in vivo. Here, we report an in vivo RNA interference screen in Drosophila melanogaster targeting all 45 DUBs that we annotated in the fly genome. We show that at least four DUBs function specifically in the formation of the fly wing margin and/or the specification of the scutellar sensory organ precursors, two processes that are strictly dependent on the balanced Notch signaling activity. Furthermore, we provide genetic evidence suggesting that these DUBs are necessary to positively modulate Notch signaling activity. Our study reveals a conserved molecular mechanism by which protein deubiquitination process contributes to the complex posttranslational regulation of Notch signaling in vivo.