-A spatial association between mast cells and nerves has been described in both the gastrointestinal and genitourinary tracts. However, the factors that influence the anatomic relationship between mast cells and nerves have not been completely defined. It has been suggested that the high-affinity receptor for substance P [neurokinin-1 (NK1)] might modulate this interaction. We therefore assessed mast cell-nerve relationships in tissues isolated from wild-type and NK1 receptor knockout (NK1 Ϫ/Ϫ ) mice. We now report that, in the complete absence of NK1 receptor expression, there is a significant increase in the number of mast cells without a change in the anatomic relationship between mast cell and nerves in stomach and bladder tissues at the light microscopic level. We next determined whether transplanted mast cells would maintain their spatial distribution, number, and contact with nerve elements. For this purpose, mast cell-deficient Kit W /Kit WϪv mice were reconstituted with wild-type or NK1 Ϫ/Ϫ bone marrow. No differences in mast cell-nerve contact were observed. These results suggest that NK1 receptor expression is important in the regulation of the number of mast cells but is not important in the interaction between mast cells and nerves. Furthermore, the interaction between mast cells and nerves is not mediated through NK1 receptor expression on the mast cell. Further studies are needed to determine the molecular pathway involved in mast cell migration and interaction with nerve elements, but the model of reconstitution of Kit W /Kit WϪv mice with mast cells derived from different genetically engineered mice is a useful approach to further explore these mechanisms. cystitis; substance P; disease animal model MAST CELLS ARE NORMALLY DISTRIBUTED throughout mucosal surfaces in proximity to blood vessels (21), lymphatics (56), peripheral nerves (22), and epithelial cells. This pattern of distribution facilitates the exposure of mast cells to stimuli, such as soluble protein, antigens (26), or neuropeptides (10), that can induce activation. Furthermore, it places the mast cell at the interface of potentially critical host-pathogen interactions (6, 28) and in turn makes their cell products available to a variety of cell types in the microenvironment, including sensory and autonomic nerves (22,47,48) and smooth muscle cells (16 -18).Spatial associations in biological systems are often indicative of functional interactions. In this context, nerve-mast cell interaction has been described in the skin and in the gastrointestinal (GI) and urinary tracts (4, 30, 33, 50). Early studies elegantly described the nonrandom spatial association of mast cells with nerves in a variety of tissues in which actual membrane-membrane contacts occur (11,22,32,44,47,48). In the GI tract, several studies have suggested that mast cell-nerve interaction has an important homeostatic role in the regulation of gut physiology as well pathophysiology (57). Studies that have utilized mast cell-deficient Kit W /Kit WϪv (Kit) mice have provide...