Osr1 orchestrates lymph node initiation and vasculature formation during embryogenesis and its role in adult lymph nodes

• Applicant: Dr. Pedro Vallecillo García
• Subject Area: Developmental Biology ; Immunology
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 407611767

Secondary lymph organs emerge at specific sites of the body during development by the interaction of local mesenchymal lymphoid tissue organizer cells (LTos) that attract lymphoid tissue inducer cells (LTis). The source and type of signals involved in the commitment of embryonic LTo precursors to specified organizer cells able to attract LTi cells remain obscure. We have found that the transcription factor Odd-skipped related gene 1 (Osr1) is expressed in mesenchymal cells of embryonic lymph node primordia and the surrounding mesenchyme. Loss of function studies revealed an essential function of Osr1 orchestrating lymph node initiation and the formation of lymph vasculature during embryogenesis. Osr1 KO embryos failed to form lymph node anlagen, the attraction of CD4+ cells by LTo cells via CXCL13 was abrogated. Lymph endothelial cells (LECs) showed a decreased proliferation rate and failed to form lymph vessels, in line with reduced expression of Vascular Endothelial Growth Factor C (VEGFC) by Osr1-deficient cells. We propose that Osr1 marks embryonic LTo progenitors and functional LTOs, and that Osr1 is essential for the commitment and function of LTos during lymph node initiation. Using lineage tracing experiments we revealed that early embryonic Osr1+ LTo cells give rise to a significant proportion of adult lymph node fibroblasts (follicular reticular cells, FRCs) and that these cells are maintained throughout embryogenesis and adult life. Furthermore, we showed that Osr1 expression persists in a subpopulation of fibroblastic reticular cells (FRCs) found in the medulla zone of adult lymph nodes that are closely associated with lymph vessels. In addition, Osr1 expression is re-activated in FRCs during the process of inflammation anticipating an important role of Osr1+ FRCs that might reacquire embryonic functions during inflammatory processes.In this proposal, we aim to shed light on the signals that lead to the commitment of LTo precursors and the mechanisms to attract of the first CD4+ cells to the lymph node primordium and to define the role of the transcription factor Osr1 therein. Secondly, we will exploit our genetic tools to investigate the role of Osr1 in adult FRCs generating new insight into their function in resting lymph nodes as well during inflammation.

• DFG Programme: Research Grants