biostudies-literatureO'Connor KWNIAID NIH HHSNHLBI NIH HHSHHS | NIH | National Institute of Allergy and Infectious DiseasesNCI NIH HHSDivision of Intramural Research, National Institute of Allergy and Infectious Diseasese2220853120https://www.ebi.ac.uk/biostudies/studies/S-EPMC10469339biostudies-literatureUnknown120(35)Ly6C^lo monocytes are a myeloid subset that specializes in the surveillance of vascular endothelium. Ly6C^lo monocytes have been shown to derive from Ly6C^hi monocytes. NOTCH2 signaling has been implicated as a trigger for Ly6C^lo monocyte development, but the basis for this effect is unclear. Here, we examined the impact of NOTCH2 signaling of myeloid progenitors on the development of Ly6C^lo monocytes in vitro. NOTCH2 signaling induced by delta-like ligand 1 (DLL1) efficiently induced the transition of Ly6C^hi TREML4^- monocytes into Ly6C^lo TREML4⁺ monocytes. We further identified two additional transcriptional requirements for development of Ly6C^lo monocytes. Deletion of BCL6 from myelProceedings of the National Academy of Sciences of the United States of America<i>Bcl6</i>, <i>Irf2</i>, and <i>Notch2</i> promote nonclassical monocyte development.PMC10469339R01AI162643R01 CA248919R21 AI164142R01 AI162643R01 HL140622R01AI150297R01 AI150297Kim SGeorgopoulos KBriseno CGO'Connor KWMurphy TLLiu TMurphy KMfalse<i>Bcl6</i>, <i>Irf2</i>, and <i>Notch2</i> promote nonclassical monocyte development.Ly6C^lo monocytes are a myeloid subset that specializes in the surveillance of vascular endothelium. Ly6C^lo monocytes have been shown to derive from Ly6C^hi monocytes. NOTCH2 signaling has been implicated as a trigger for Ly6C^lo monocyte development, but the basis for this effect is unclear. Here, we examined the impact of NOTCH2 signaling of myeloid progenitors on the development of Ly6C^lo monocytes in vitro. NOTCH2 signaling induced by delta-like ligand 1 (DLL1) efficiently induced the transition of Ly6C^hi TREML4^- monocytes into Ly6C^lo TREML4⁺ monocytes. We further identified two additional transcriptional requirements for development of Ly6C^lo monocytes. Deletion of BCL6 from myel2023-01-01T00:00:00Z2023 Aug2025-04-18T13:13:44.816Z2025-04-06T22:45:54.987ZS-EPMC104693393760722310.1073/pnas.2220853120