Dual functions of cell-autonomous and non-cell-autonomous ADAM10 activity in granulopoiesis.

Previous studies have revealed various extrinsic stimuli and factors involved in the regulation of hematopoiesis. Among these, Notch-mediated signaling has been suggested to be critically involved in this process. Herein, we show that conditional inactivation of ADAM10, a membrane-bound protease with a crucial role in Notch signaling (S2 cleavage), results in myeloproliferative disorder (MPD) highlighted by severe splenomegaly and increased populations of myeloid cells and hematopoietic stem cells. Reciprocal transfer of bone marrow cells between wild-type and ADAM10 mutant mice revealed that ADAM10 activity in both hematopoietic and nonhematopoietic cells is involved in the development of MPD. Notably, we found that MPD caused by lack of ADAM10 in nonhematopoietic cells was mediated by G-CSF, whereas MPD caused by ADAM10-deficient hematopoietic cells was not. Taken together, the present findings reveal previously undescribed nonredundant roles of cell-autonomous and non-cell-autonomous ADAM10 activity in the maintenance of hematopoiesis.

[1]  O. Abdel-Wahab,et al.  A novel tumor suppressor function for the Notch pathway in myeloid leukemia , 2011, Nature.

[2]  C. Blobel,et al.  The disintegrin/metalloproteinase Adam10 is essential for epidermal integrity and Notch-mediated signaling , 2011, Development.

[3]  C. Guidos,et al.  Functions of notch signaling in the immune system: consensus and controversies. , 2010, Annual review of immunology.

[4]  D. Conrad,et al.  ADAM10 is essential for Notch2-dependent marginal zone B cell development and CD23 cleavage in vivo , 2010, The Journal of experimental medicine.

[5]  W. Leonard,et al.  Atopic Dermatitis-Like Disease and Associated Lethal Myeloproliferative Disorder Arise from Loss of Notch Signaling in the Murine Skin , 2010, PloS one.

[6]  L. Calvi,et al.  Notch signaling and the bone marrow hematopoietic stem cell niche. , 2010, Bone.

[7]  P. V. van Diest,et al.  Metalloprotease ADAM10 Is Required for Notch1 Site 2 Cleavage* , 2009, The Journal of Biological Chemistry.

[8]  Sun-Hee Kim,et al.  Defective Notch activation in microenvironment leads to myeloproliferative disease. , 2008, Blood.

[9]  Jeongsup Shim,et al.  Notch-dependent control of myelopoiesis is regulated by fucosylation. , 2008, Blood.

[10]  大沢 匡毅.  Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell , 2007 .

[11]  K. Horiuchi,et al.  Cutting Edge: TNF-α-Converting Enzyme (TACE/ADAM17) Inactivation in Mouse Myeloid Cells Prevents Lethality from Endotoxin Shock1 , 2007, The Journal of Immunology.

[12]  J. Aster,et al.  Canonical notch signaling is dispensable for the maintenance of adult hematopoietic stem cells. , 2005, Cell stem cell.

[13]  U. Suter,et al.  Jagged1-dependent Notch signaling is dispensable for hematopoietic stem cell self-renewal and differentiation. , 2005, Blood.

[14]  Hui Zheng,et al.  Myeloproliferative disease in mice with reduced presenilin gene dosage: effect of gamma-secretase blockage. , 2004, Biochemistry.

[15]  Eric C. Lai,et al.  Notch signaling: control of cell communication and cell fate , 2004, Development.

[16]  D. Scadden,et al.  Osteoblastic cells regulate the haematopoietic stem cell niche , 2003, Nature.

[17]  B. de Strooper,et al.  The disintegrin/metalloprotease ADAM 10 is essential for Notch signalling but not for alpha-secretase activity in fibroblasts. , 2002, Human molecular genetics.

[18]  D. Scadden,et al.  Notch1 activation increases hematopoietic stem cell self-renewal in vivo and favors lymphoid over myeloid lineage outcome. , 2002, Blood.

[19]  I. Bernstein,et al.  Pluripotent, cytokine-dependent, hematopoietic stem cells are immortalized by constitutive Notch1 signaling , 2000, Nature Medicine.

[20]  A Cumano,et al.  A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE. , 2000, Molecular cell.

[21]  H. Macdonald,et al.  Deficient T cell fate specification in mice with an induced inactivation of Notch1. , 1999, Immunity.

[22]  David C. Lee,et al.  An essential role for ectodomain shedding in mammalian development. , 1998, Science.

[23]  I. Bernstein,et al.  The Notch ligand, Jagged-1, influences the development of primitive hematopoietic precursor cells. , 1998, Blood.

[24]  D. Link,et al.  Impaired production and increased apoptosis of neutrophils in granulocyte colony-stimulating factor receptor-deficient mice. , 1996, Immunity.

[25]  A. Murray,et al.  Association of Spindle Assembly Checkpoint Component XMAD2 with Unattached Kinetochores , 1996, Science.

[26]  M Aguet,et al.  Inducible gene targeting in mice , 1995, Science.