WNT factors represent key mediators of many processes in animal development and homeostasis and act through a receptor complex comprised of members of the Frizzled and low density lipoprotein-related receptors (LRP). In mammals, 19 genes encoding Wingless and Int-related factor (WNTs), 10 encoding Frizzled, and 2 encoding LRP proteins have been identified, but little is known of the identities of individual Frizzled-LRP combinations mediating the effects of specific WNT factors. Additionally, several secreted modulators of WNT signaling have been identified, including at least three members of the Dickkopf family. WNT7A is a WNT family member expressed in the vertebrate central nervous system capable of modulating aspects of neuronal plasticity. Gene knock-out models in the mouse have revealed that WNT7A plays a role in cerebellar maturation, although its function in the development of distal limb structures and of the reproductive tract have been more intensely studied. To identify a receptor complex for this WNT family member, we have analyzed the response of the rat pheochromocytoma cell line PC12 to WNT7A. We find that PC12 cells are capable of responding to WNT7A as measured by increased -catenin stability and activation of a T-cell factor-based luciferase reporter construct and that these cells express three members of the Frizzled family (Frizzled-2, -5, and -7) and LRP6. Our functional analysis indicates that WNT7A can specifically act via a Frizzled-5⅐LRP6 receptor complex in PC12 cells and that this activity can be antagonized by Dickkopf-1 and Dickkopf-3.Members of the WNT gene family encode structurally related secreted glycoprotein factors, modulating a vast array of processes during vertebrate and invertebrate embryonic development as well as several aspects of tissue homeostasis in the adult (1-4). In embryos, signaling by WNT factors controls the organization of the body plan during the early stages of development as well as organogenesis at later developmental stages. Postnatally, WNT signaling is involved in normal biological events such as tissue maturation and homeostasis and in several neoplastic pathologies (2, 5-8). For example, in the mammalian central nervous system (CNS) 1 WNT signal transduction is involved in neural induction and patterning in early embryogenesis (2, 4) as well as in organogenesis and neuronal homeostasis at later stages (9). In the adult, WNTs play a role in the control of neuronal plasticity and are implicated in CNS neoplasias such as medulloblastoma (10 -14). The analysis of the signaling events mediated by WNTs has uncovered at least three signal transduction pathways, each involved in the mediation of specific biological responses (2, 15). The most studied and best understood signaling cascade elicited by WNTs involves an interaction with a receptor complex comprising members of the Frizzled (FZD) class of 7-transmembrane receptors and a member of the low density lipoprotein receptor (LRP) family of single-pass membrane proteins (16). WNT interaction with its r...