Langerhans cells (LC) are the principal accessory cells present in epidermis. Because LC have limited capacity for self-renewal, epidermis is continually repopulated by as-yet uncharacterized bone marrow-derived LC progenitors. In addition, although LC persist in epidermis for extended periods, LC are induced to migrate from skin to regional lymph nodes after antigen exposure. To begin to elucidate mechanisms involved in LC trafficking, we characterized LC-keratinocyte (KC) interactions. Here we report that fresh murine LC express cadherins, and that LC adhere to KC in vitro through E-cadherin. Cultured LC (which may bear a phenotypic and functional relationship to LC that have migrated to lymph nodes) express lower levels of E-cadherin and exhibit decreased affinity for KC. These results suggest that expression of E-cadherin by LC promotes persistence of these cells in epidermis, and that cadherins may play important and unanticipated roles in interactions between leukocytes and epithelia.

The expression of DCC (deleted in colorectal cancer) is often markedly reduced in colorectal and other cancers. However, the rarity of point mutations identified in DCC coding sequences and the lack of a tumor predisposition phenotype in DCC hemizygous mice have raised questions about its role as a tumor suppressor. DCC also mediates axon guidance and functions as a dependence receptor; such receptors create cellular states of dependence on their respective ligands by inducing apoptosis when unoccupied by ligand. We now show that DCC drives cell death independently of both the mitochondria-dependent pathway and the death receptor͞caspase-8 pathway. Moreover, we demonstrate that DCC interacts with both caspase-3 and caspase-9 and drives the activation of caspase-3 through caspase-9 without a requirement for cytochrome c or Apaf-1. Hence, DCC defines an additional pathway for the apoptosome-independent caspase activation. V ogelstein and his colleagues (1) have shown that the development of colonic carcinoma from normal colonic epithelium is associated with the mutation of a specific set of genes. Allelic deletions (loss of heterozygosity) on chromosome 18q in more than 70% of primary colorectal tumors prompted the search for a tumor suppressor gene at that locus. This search led to the cloning of a putative cell-surface receptor, DCC (deleted in colorectal cancer) (1). DCC expression was then shown to be markedly reduced in more than 50% of colorectal tumors. Moreover, the loss of DCC expression is not restricted to colon carcinoma but has been observed in other tumor types, including carcinoma of the stomach, pancreas, esophagus, prostate, bladder, breast, male germ cell tumors, neuroblastomas, gliomas, and some leukemias (2, 3). However, proof that DCC is a tumor suppressor gene remains inconclusive (4, 5).DCC encodes an approximately 200-kDa type I membrane protein of 1,447 amino acids, which displays homology in its extracellular domain with cell adhesion molecules (2), suggesting that DCC may play a role in cell-cell or cell-matrix interactions (6). However, DCC-mediated cell aggregation has not been firmly established (7). Recently, Tessier-Lavigne and collaborators (8, 9) have suggested that DCC may function as a component of a receptor complex that mediates the effects of the axonal chemoattractant netrin-1. The role of DCC in mediating growth cone extension has been supported by the analysis of the DCC knockout mice, which display abnormal brain development (4). However, the signaling transduction of netrin-1 through DCC that results in axon outgrowth is mainly unknown. In response to netrin-1 binding, DCC has been shown to interact with other netrin-1 receptors like UNC5H (i.e., three members UNC5H1, -2, and -3) (10) or the adenosine A2b receptor shown to transduce cAMP production upon netrin-1 binding (11). Recently, it also has been proposed that Frazzled, the Drosophila ortholog of DCC, is not, in certain circumstances, a transducing receptor but rather a carrier for the cue netrin-1 that allows netr...

The RET (rearranged during transfection) proto-oncogene encodes a tyrosine kinase receptor involved in both multiple endocrine neoplasia type 2 (MEN 2), an inherited cancer syndrome, and Hirschsprung disease (HSCR), a developmental defect of enteric neurons. We report here that the expression of RET receptor induces apoptosis. This pro-apoptotic effect of RET is inhibited in the presence of its ligand glial cell line-derived neurotrophic factor (GDNF). Furthermore, we present evidence that RET induces apoptosis via its own cleavage by caspases, a phenomenon allowing the liberation/exposure of a pro-apoptotic domain of RET. In addition, we report that Hirschsprung-associated RET mutations impair GDNF control of RET pro-apoptotic activity. These results indicate that HSCR may result from apoptosis of RET-expressing enteric neuroblasts.