Jedi—a novel transmembrane protein expressed in early hematopoietic cells

Abstract

Self-renewal and differentiation of hematopoietic stem and progenitor cells are defined by the ensembles of genes expressed by these cells. Here we report identification of a novel gene named Jedi, which is expressed predominantly in short- and long-term repopulating stem cells when compared to more mature bone marrow progenitors. Jedi mRNA encodes a transmembrane protein that contains multiple EGF-like repeats. Jedi and two earlier reported proteins, MEGF10 and MEGF11, share a substantial homology and are likely to represent a novel protein family. Studies of the potential role of Jedi in hematopoietic regulation demonstrated that the retrovirally mediated expression of Jedi in bone marrow cells decreased the number of myeloid progenitors in in vitro clonogenic assays. In addition, expression of Jedi in NIH 3T3 fibroblasts resulted in a decreased number of late and early myeloid progenitors in the non-adherent co-cultured bone marrow cells. Jedi shares a number of structural features with the Jagged/Serrate/Delta family of Notch ligands, and our experiments indicate that the extracellular domain of Jedi, similar to the corresponding domain of Jagged1, inhibits Notch signaling. On the basis of obtained results, we suggest that Jedi is involved in the fine regulation of the early stages of hematopoietic differentiation, presumably through the Notch signaling pathway.

PEAR1 attenuates megakaryopoiesis via control of the PI3K/PTEN pathway

“…Moreover, the ectopic expression of Pear1 in NIH 3T3 fibroblasts reduced both early and late myeloid progenitors in nonadherent cocultured bone marrow cells. 3 It is not clear whether this loss is caused by apoptosis or artificial signaling coupled to excessive PEAR phosphorylation. 1 We therefore investigated the role of PEAR1 in megakaryopoiesis by reducing its expression in 2 distinct models based on expression depletion.…”

“…1 In addition to its role in platelet function, a potential role for PEAR1 in hematopoietic cell regulation has been proposed. 3 The stable overexpression of PEAR1 in mouse bone marrow cells using retroviral vectors decreased the number of myeloid progenitors during in vitro clonogenic assays, suggesting that PEAR1 regulates the early stages of hematopoietic differentiation. 3 Whether PEAR1 is also a determinant of megakaryocyte (MK) differentiation is presently unclear.…”

Canonical and Non-Canonical Notch Ligands

“…A putative DSL ligand-like protein called Jagged and Delta protein (Jedi) has been identified based on sequence data (Krivtsov et al, 2007). However, the putative DSL and EGF repeats of Jedi lack the conserved cysteine spacing common to either the signature motif of canonical ligands or EGF repeats present in DNER and Dlk-1.…”

“…However, the putative DSL and EGF repeats of Jedi lack the conserved cysteine spacing common to either the signature motif of canonical ligands or EGF repeats present in DNER and Dlk-1. Instead, the Jedi ECD contains an N-terminal emilin domain followed by multiple tandem repeats of an 8-cysteine variation of the EGF domain interspersed with two single 6-cysteine EGF repeats (Krivtsov et al, 2007; Nanda et al, 2005). In fact, Jedi has not been reported to interact with any of the Notch receptors and lacks trans -activating or cis -inhibitory activity.…”

“…Although soluble Jedi added to Notch-expressing cells weakly inhibits a Notch reporter, there is currently no strong evidence linking Jedi to Notch signaling. The closely related Jedi family member, multiple EGF-like domains 10 protein (MEGF10) (Krivtsov et al, 2007) has also been proposed to interact with the Notch signaling pathway (Holterman et al, 2007); however, like Jedi, there has been no formal demonstration that MEGF10 can directly interact with Notch receptors.…”