TGF-b receptor; Gene-Targeting; Microglia; mononuclear phagocyte system; Csf-1 receptor; EAE; Glioma; Sall1; Homeostasis; Development; CNS
Buttgereit Anne, Lelios Iva, Yu Xueyang, Vrohlings Melissa, Krakoski Natalie R, Gautier Emmanuel L, Nishinakamura Ryuichi, Becher Burkhard, Greter Melanie (2016), Sall1 is a transcriptional regulator defining microglia identity and function, in Nature Immunology
, 2016(12), 1397-1406.
The mononuclear phagocyte system (MPS) comprises a network of distinct myeloid cells including monocytes, macrophages and dendritic cells, which are heterogeneous in their origin, development and function. Microglia are the resident macrophages of the central nervous system (CNS) and are considered the immune sentinels of the CNS. Like other macrophages, microglia greatly contribute to the maintenance of tissue homeostasis. Besides being implicated in CNS pathologies, recent evidence suggests that they are also crucial for neurogenesis during embryonic development and in the adult. A growing number of phenotypic markers and lineage-guiding factors exist for defining different members of the MPS. However due to the lack of a truly unique marker for microglia, microglia-specific gene-targeting was never achieved without the collateral targeting of other members of the MPS, which often results in mortality. This research proposal aims to gain a deeper insight into microglia biology and their functional specializations in health and disease.After a transcriptome analysis of all known MPS members, we identified a microglia-specific gene, Sall1. This gene encodes a transcription factor with unknown function in microglial cells. Using Sall1CreER, Sall1fl/fl and Sall1GFP mice, we will for the first time be able to genetically manipulate microglia in vivo to gain a greater understanding of previously unappreciated functions of microglia in homeostasis, CNS disease and tumor rejection. In addition, we aim to determine the role of Sall1 itself during microglia development, maintenance and function under physiological and inflammatory conditions.