The Delta intracellular domain mediates TGF-β/Activin signaling through binding to Smads and has an important bi-directional function in the Notch–Delta signaling pathway

Abstract

Delta is a major transmembrane ligand for Notch receptor that mediates numerous cell fate decisions. The Notch signaling pathway has long been thought to be mono-directional, because ligands for Notch were generally believed to be unable to transmit signals into the cells expressing them. However, we showed here that Notch also supplies signals to neighboring mouse neural stem cells (NSCs). To investigate the Notch–Delta signaling pathway in a bi-directional manner, we analyzed functional roles of the intracellular domain of mouse Delta like protein 1 (Dll1IC). In developing mouse NSCs, Dll1IC, which is released from cell membrane by proteolysis, is present in the nucleus. Furthermore, we screened for transcription factors that bind to Dll1IC and demonstrated that Dll1IC binds specifically to transcription factors involved in TGF-β/Activin signaling—Smad2, Smad3 and Smad4—and enhances Smad-dependent transcription. In addition, the results of the present study indicated that over-expression of Dll1IC in embryonic carcinoma P19 cells induced neurons, and this induction was blocked by SB431542, which is a specific inhibitor of TGF-β/Activin signaling. These observations strongly suggested that Dll1IC mediates TGF-β/Activin signaling through binding to Smads and plays an important role for bi-directional Notch–Delta signaling pathway.

Bile acids induce Delta-like 1 expression via Cdx2-dependent pathway in the development of Barrett's esophagus

“…22,23 Intracellular interaction between Notch ligands and Notch was shown to inhibit Notch signaling. [22][23][24][25] Therefore, Dll1, a Notch ligand, may function as both a Notch signaling agonist and antagonist in the development of BE. If Dll1 functions as a canonical Notch ligand, then the Notch receptor is cleaved by gamma-secretase and metalloprotease, while the downstream transcription factor Hes1 is induced and ATOH1 expression is suppressed.…”

“…Taken together with our previous findings, 13 our present results show a novel function of Dll1 to promote the development of intestinal metaplasia induced by bile acids in a Cdx2-dependent manner (Figure 8). Recent findings have consistently indicated that the intracellular domains of Notch ligands function as transcriptional co-activators 24 and facilitate transcription of various genes, [23][24][25] including ATOH1, Cdx2, and MUC2. Nonetheless, further research is required for elucidation of the precise role of Dll1 as a regulator of intracellular transcription in BE development.…”

Regulation of Notch1 Signaling by Delta-like Ligand 1 Intracellular Domain through Physical Interaction

“…3B). Previous studies have demonstrated that Dll1-IC was present in the nuclei of developing neural stem cells (NCS) after being released from the cell membrane by gamma-secretase (Hiratochi et al, 2007). Additionally, Notch1-IC is located predominantly within the nucleus.…”

“…Evidence has recently been accumulating in support of a functional role of the intracellular domains of Notch ligands, which would imply downstream signal transduction. Dll1-IC has been shown to bind to smad2/3, thereby mediating transforming growth factor-b (TGF-b)/Activin signaling (Hiratochi et al, 2007). Thus, it has been previously reported that the lacking intracellular domain of Delta (X-Delta) affects normal development in Xenopus (Chitnis, 1995;Hiratochi et al, 2007;Sun and Artavanis-Tsakonas, 1996).…”

“…Dll1-IC has been shown to bind to smad2/3, thereby mediating transforming growth factor-b (TGF-b)/Activin signaling (Hiratochi et al, 2007). Thus, it has been previously reported that the lacking intracellular domain of Delta (X-Delta) affects normal development in Xenopus (Chitnis, 1995;Hiratochi et al, 2007;Sun and Artavanis-Tsakonas, 1996). It has also been demonstrated that Dll1-IC functions as an antagonist of Notch signaling in Drosophila (Sun and Artavanis-Tsakonas, 1996).…”