Stem cell factor (SCF; also known as kit ligand, mast cell ultimate destinations during development. Hematopoietic cells growth factor, or steel factor) is a hematopoietic cytokine expressing the c-kit receptor protein were detected at gestathat triggers its biologic effects by binding to its receptor, tional day 8 in the embryonic yolk sac and by day 10 in fetal c-kit. 2-5 A host of naturally occurring mutations at the Sl liver, where they progressively increased until day 15 and then locus or at the W locus, which encode SCF and the c-kit decreased, 19 paralleling the transition from yolk sac to fetal receptor, respectively, has been identified6, 7 and molecularly liver to bone marrow hematopoiesis. Fetal thymus also concharacterized (reviewed in Besmer et al8). These mutations tains c-kit receptor-positive primitive T-lymphocyte and B-provide insights into the role of SCF and the c-kit receptor lymphocyte progenitors. 19 Although the brain and spinal cord in vivo. Absence of SCF protein (the Sl mutation) or absence develop normally in mice with mutations at the Sl or W loci, of cell surface c-kit receptor display (the W mutation) result these mice demonstrate subtle learning and memory defects. 20 in death in utero or in the perinatal period with severe macro-In addition to its essential role during development, SCF cytic anemia. Absence of c-kit receptor kinase activity (the is also important during adult life. Treatment of adult mice W42 mutation) 9 also causes perinatal death with severe macwith a neutralizing anti–c-kit receptor monoclonal antibody rocytic anemia. These observations indicate that SCF plays (ACK2) causes pancytopenia and markedly decreases bone an essential role during development in utero. marrow cellularity, 21 suggesting that constitutive production Point mutations in the c-kit receptor that diminish its tyroof SCF by marrow endothelial cells and fibroblasts22, 23 may sine kinase activity or mutations that alter SCF production be required for maintenance of normal basal hematopoiesis. are associated with a spectrum of phenotypic abnormalities, SCF is also required for acute erythroid expansion during including variable degrees of macrocytic anemia, decreased recovery from hemolytic anemia in adult mice. 24 Spermatonumbers of tissue mast cells, decreased fertility, and de- genesis, 25 melanocyte development, 26 gut motility, 12 and recreased pigmentation. 10 These observations demonstrate a sponse to intestinal helminth infection27 are impaired by role for SCF and its receptor c-kit in hematopoiesis and in ACK2 antibody treatment. development of germ cells and melanocytes. Development This review will briefly discuss the production and strucof the interstitial cells of Cajal, which are responsible for ture of SCF and will focus on the physiologic role of SCF intestinal pacemaker activity, is defective in mice with muta- in hematopoiesis. The cellular distribution of the c-kit receptions at the Sl or W loci. 11, 12 In general, the severity of the tor will also be described. Potential clinical uses for SCF defect in c-kit receptor kinase activity parallels the severity and therapeutic approaches based on the c-kit receptor will of the phenotypic abnormalities that result. 13 be discussed. SCF is normally found in both soluble and transmembrane