A major component of the research in my laboratory focuses on regulation of the proliferation and differentiation of mononuclear phagocytes, osteoclasts and hematopoietic and neural stem cells mediated by the colony stimulating factor-1 (CSF-1) receptor (CSF-1R) . The CSF-1R is a class III receptor tyrosine kinase. CSF-1 is expressed as a secreted glycoprotein, secreted proteoglycan or a membrane-spanning, cell-surface glycoprotein. CSF-1-deficient mice are osteopetrotic due to a lack of osteoclasts, have poor fertility and several other defects related to CSF-1 regulation of macrophages that have critical scavenger and trophic roles in the development, maintenance or function of tissues in which they reside.
The developmental and physiological roles of CSF-1 are being studied using CSF-1- and CSF-1R-deficient mice, coupled with transgenic approaches. CSF-1 regulation of macrophages is also important in innate immunity, inflammatory diseases, atherosclerosis, and obesity. CSF-1 regulation of tumor-associated macrophages enhances solid tumor progression and metastasis. Mouse genetic and other approaches are being taken to investigate the role of the CSF-1 isoforms in disease development.
In addition, we are studying the biology and action of a novel ligand for the CSF-1R, interleukin-34 (IL-34), which we believe explains the greater severity of the CSF-1R-deficiency, compared with CSF-1 deficiency. Additional studies focus on the mechanisms of CSF-1R signal transduction, using a combination of genetic and proteomic approaches and the function of downstream signaling molecules.
Lastly, we study the role of the Shark tyrosine kinase in the regulation of embryonic dorsal closure and the recognition and engulfment of dying neurons in Drosophila.
Chitu V, Ferguson PJ, de Bruijn R, Schlueter AJ, Ochoa LA, Waldschmidt TJ, Yeung YG, Stanley ER. Primed innate immunity leads to autoinflammatory disease in PSTPIP2-deficient cmo mice. Blood. 2009 Sep 17;114(12):2497-505.
Huynh D, Dai XM, Nandi S, Lightowler S, Trivett M, Chan CK, Bertoncello I, Ramsay RG, Stanley ER. Colony stimulating factor-1 dependence of paneth cell development in the mouse small intestine. Gastroenterology. 2009 Jul;137(1):136-44, 144.e1-3.
Yu W, Chen J, Xiong Y, Pixley FJ, Dai XM, Yeung YG, Stanley ER. CSF-1 receptor structure/function in MacCsf1r-/- macrophages: regulation of proliferation, differentiation, and morphology. J Leukoc Biol. 2008 Sep;84(3):852-63.
Ziegenfuss JS, Biswas R, Avery MA, Hong K, Sheehan AE, Yeung YG, Stanley ER, Freeman MR. Draper-dependent glial phagocytic activity is mediated by Src and Syk family kinase signalling. Nature. 2008 Jun 12;453(7197):935-9.
Chitu V, Stanley ER. Pombe Cdc15 homology (PCH) proteins: coordinators of membrane-cytoskeletal interactions. Trends Cell Biol. 2007 Mar;17(3):145-56. Review.
Nandi S, Akhter MP, Seifert MF, Dai XM, Stanley ER. Developmental and functional significance of the CSF-1 proteoglycan chondroitin sulfate chain. Blood. 2006 Jan 15;107(2):786-95.
Chitu V, Stanley ER. Colony-stimulating factor-1 in immunity and inflammation. Curr Opin Immunol. 2006 Feb;18(1):39-48. Review.
Chitu V, Pixley FJ, Macaluso F, Larson DR, Condeelis J, Yeung YG, Stanley ER. The PCH family member MAYP/PSTPIP2 directly regulates F-actin bundling and enhances filopodia formation and motility in macrophages. Mol Biol Cell. 2005 Jun;16(6):2947-59.
Pixley FJ, Stanley ER. CSF-1 regulation of the wandering macrophage: complexity in action. Trends Cell Biol. 2004 Nov;14(11):628-38. Review
Dai XM, Zong XH, Sylvestre V, Stanley ER. Incomplete restoration of colony-stimulating factor 1 (CSF-1) function in CSF-1-deficient Csf1op/Csf1op mice by transgenic expression of cell surface CSF-1. Blood. 2004 Feb 1;103(3):1114-23.
Dai XM, Zong XH, Akhter MP, Stanley ER. Osteoclast deficiency results in disorganized matrix, reduced mineralization, and abnormal osteoblast behavior in developing bone. J Bone Miner Res. 2004 Sep;19(9):1441-51.
Dai XM, Ryan GR, Hapel AJ, Dominguez MG, Russell RG, Kapp S, Sylvestre V, Stanley ER. Targeted disruption of the mouse colony-stimulating factor 1 receptor gene results in osteopetrosis, mononuclear phagocyte deficiency, increased primitive progenitor cell frequencies, and reproductive defects. Blood. 2002 Jan 1;99(1):111-20.