Notch Signaling During Human T cell Development

Specific Notch receptor–ligand interactions control human TCR-ab/gd development by inducing differential Notch signal strength

“…Here, we demonstrate that the weak Notch signal that is induced by Jagged1 is capable of generating DP and TCR- + CD3 + thymocytes from uncommitted postnatal thymocytes from humanin agreement with previous observations (Dontje et al, 2006;Van de Walle et al, 2009)-but not from mouse. Consistently, we show that Jagged1 does not support  T cell development in human, whereas this ligand is sufficient for murine TCR- T cell differentiation, illustrating the opposing Notch signaling requirements between mouse and human (Taghon and Rothenberg, 2008;Taghon et al, 2012). This difference corresponds with a differential Notch activation status during intrathymic T cell development between mouse and human as illustrated by the expression levels of Notch target genes in both species.…”

“…These studies will be required to define the precise contributions of TCR and Notch signal strengths in mediating the -versus -lineage choice in human. Nevertheless, based on the current evidence from in vitro studies using mouse and human ex vivo-isolated progenitors, it is clear that the requirements for Notch signaling during the early stages of T cell development are distinct between both species (Taghon et al, 2012). The results in this manuscript indicate that this may occur at the level of TCR generation.…”

“…One of the most important signaling cascades during early T cell development comprises the Notch signaling pathway and it is well established that the  versus  T cell lineage choice is modulated by differential Notch signal strength in both mouse and human (Taghon and Rothenberg, 2008;Ciofani and Zúñiga-Pflücker, 2010;Kreslavsky et al, 2010;Taghon et al, 2012). However, it has remained unclear which receptor-ligand interactions are involved in these processes and, moreover, the Notch dependency for TCR- and TCR- T cell development was shown to be different between both species (Washburn et al, 1997;De Smedt et al, 2002;García-Peydró et al, 2003;Ciofani et al, 2006;Garbe et al, 2006;Taghon et al, 2006;Van de Walle et al, 2009).…”

Notch3 Activation Is Sufficient but Not Required for Inducing Human T-Lineage Specification

“…Because species differences exist, studies in human are of critical translational importance. Indeed, previous work from our laboratory and others, although mostly limited to pan-Notch activation and inhibition experiments, confirmed certain roles for Notch activation in early hematopoietic lineage decisions (15)(16)(17)(18), but also revealed some subtle differences during intrathymic stages of T cell development (16,(19)(20)(21)(22). In more recent work, we revealed a critical role for Jagged2-mediated Notch3 activation in human TCR-gd T cell development (23), a mechanism that seems absent in mouse (24,25).…”

Notch Signaling Is Involved in Neurogenic Commitment of Human Periodontal Ligament-Derived Mesenchymal Stem Cells

“…The discrepancies in observations regarding the role of Notch signaling in neurogenic differentiation may have several explanations. First, it has been shown that function of Notch signaling is cell type and developmental stage specific [37,38]. In this regard, a differential expression of Notch receptors was noted at different stages of development, which may influence intracellular signaling and cell fate decision [39,40].…”