Moreover a ligand for fusin has recently been found

Moreover, a ligand for fusin has recently been found: the lymphocyte chemoattractant stromal-derived factor-1 (SDF-1) binds to CHO Ursodiol mg transfected with fusin and promotes secondary messenger production (Bleul et al., 1996; Oberlin et al., 1996). A new name, CXCR-4, has been proposed for the receptor, following the receptor nomenclature established at the 1996 Gordon Research Conference on chemotactic cytokines. Intriguingly, both the ligand SDF-1 (Shirozu et al., 1995; Tashiro et al., 1993) and the receptor fusin/CXCR-4 (Federsppiel et al., 1993) are expressed in non-hematopoietic tissues including brain, heart, kidney and lung. In fact, CXCR-4 is by far the most widely expressed of the functional chemokine receptors in non-hematopoietic cells, which suggests that there might be additional functions and/or ligands for the receptor (Bleul et al., 1996).
Materials and methods
Results
Discussion We have studied the distribution of mRNA for fusin/CXCR-4 during rat embryogenesis. This receptor is expressed early during development, starting around embryonic day 9. This contrasts with results obtained for several other 7-transmembrane receptors whose mRNA expression starts around day 14 (Quirion and Dam, 1986; Srivastava et al., 1992; Tiong and Herington, 1992; Jazin et al., 1993b; Ivgy May et al., 1994). Furthermore, the distribution of the fusin/CXC-4 receptor is widespread during development both in the immune system and in proliferative areas of the brain. No other functional chemokine receptor has such a wide distribution (Bleul et al., 1996). Moreover, fusin/CXCR-4 is very well conserved during evolution (Jazin et al., 1993a). All these observations suggest that the fusin/CXCR-4 receptor is a primordial receptor as proposed for its endogenous ligand SDF-1 (Bleul et al., 1996). The widespread distribution of the receptor supports the idea that SDF-1 may have multiple biological functions (Nagasawa et al., 1996). Alternatively, there might be additional ligands for fusin/CXCR-4. Fusin/CXCR-4 serves as a cofactor for entry of some HIV-1 isolates that are T-cell tropic. While some primary HIV-1 isolates are T-tropic and use fusin/CXCR-4 as a cofactor (Doranz et al., 1996), many isolates seem to be M-tropic and use CCR-5 (Deng et al., 1996). To evaluate the importance of CXCR-4 and CCR-5 receptors during HIV entry to CD4+ cells, the receptor required for entry of different genetic subtypes of HIV has been studied (Zhang et al., 1996). It was found that the phenotype of the virus (whether it is macrophage-tropic or T-cell tropic), rather than its genetic subtype, seems to determine second-receptor usage. Both receptors seem to be important for entry of different HIV subtypes. Also, it has been suggested that T-tropic primary HIV isolates in infected individuals are associated with CD4+ cell decline and progression to acquired immunodeficiency syndrome (AIDS) (Bleul et al., 1996). The distribution of fusin/CXCR-4 has previously been studied in adult humans where it is mainly found in the immune system and in the brain it is confined to the ependymal lining of the ventriculus (Rimland et al., 1991). Moreover, CD4 mRNA has been shown to be expressed in all brain areas and several peripheral tissues in humans and mouse (Erickson et al., 1991; Omri et al., 1994). Therefore, fusin/CXCR-4 might serve as a cofactor for HIV infection in the brain in cells that also express CD4. In fact, HIV-1 infects the brain of the majority of patients with AIDS and it has been linked to the development of a progressive dementia termed `HIV-associated dementia\' (Takahashi et al., 1996). However, the majority of infected cells have been shown to be macrophages and microglia. Studies of the distribution of possible `cofactor\' receptors and CD4 in these cells will elucidate their potential role in the pathology of the disease. We demonstrate here that the distribution of fusin/CXCR-4 is very broad and very high in rat embryos, in thymus, cerebellum, pituitary gland, olfactory bulb, olfactory epithelium, hippocampus, retina, and lungs (Fig. 3, Fig. 4). This shows that fusin/CXCR-4 is a very abundant and widespread receptor during embryogenesis and, assuming similar expression in humans, suggests the possibility of early infection of embryos during development when exposed to T-cell tropic HIV-1 isolates present in the mothers. The expression of CD4 is tightly regulated during development in mice (Andjelic et al., 1993) and it starts early during development (Doyon et al., 1994; Patel et al., 1995). The evidence for CD4 expression in brain from adult mice is unclear (Gorman et al., 1987; Lonberg et al., 1988; Omri et al., 1994) while CD4 expression in microglia in rat brain has been reported (Perry and Gordon, 1987). CD4 expression during rat development has not been studied. Therefore, additional studies should be done to evaluate the possibility that CXCR-4 and CD4 might be co-expressed in rat brain during development.