A rare type of ganglion cell in mammalian retina is directly photosensitive. These novel retinal photoreceptors express the photopigment melanopsin. They send axons directly to the suprachiasmatic nucleus (SCN), intergeniculate leaflet (IGL), and olivary pretectal nucleus (OPN), thereby contributing to photic synchronization of circadian rhythms and the pupillary light reflex. Here, we sought to characterize more fully the projections of these cells to the brain. By targeting tau-lacZ to the melanopsin gene locus in mice, ganglion cells that would normally express melanopsin were induced to express, instead, the marker enzyme beta-galactosidase. Their axons were visualized by X-gal histochemistry or anti-beta-galactosidase immunofluorescence. Established targets were confirmed, including the SCN, IGL, OPN, ventral division of the lateral geniculate nucleus (LGv), and preoptic area, but the overall projections were more widespread than previously recognized. Targets included the lateral nucleus, peri-supraoptic nucleus, and subparaventricular zone of the hypothalamus, medial amygdala, margin of the lateral habenula, posterior limitans nucleus, superior colliculus, and periaqueductal gray. There were also weak projections to the margins of the dorsal lateral geniculate nucleus. Co-staining with the cholera toxin B subunit to label all retinal afferents showed that melanopsin ganglion cells provide most of the retinal input to the SCN, IGL, and lateral habenula and much of that to the OPN, but that other ganglion cells do contribute at least some retinal input to these targets. Staining patterns after monocular enucleation revealed that the projections of these cells are overwhelmingly crossed except for the projection to the SCN, which is bilaterally symmetrical.

Four new members of the fibroblast growth factor (FGF) family, referred to as fibroblast growth factor homologous factors (FHFs), have been identified by a combination of random cDNA sequencing, data base searches, and degenerate PCR. Pairwise comparisons between the four FHFs show between 58% and 71% amino acid sequence identity, but each FHF shows less than 30%o identity when compared with other FGFs. Like FGF-1 (acidic FGF) and FGF-2 (basic FGF), the FHFs lack a classical signal sequence and contain clusters of basic residues that can act as nuclear localization signals. In transiently transfected 293 cells FHF-1 accumulates in the nucleus and is not secreted. Each FHF is expressed in the developing and adult nervous systems, suggesting a role for this branch of the FGF family in nervous system development and function.Fibroblast growth factors (FGFs) comprise a family of nine related polypeptides with broad mitogenic and cell survival activities (1-3). FGF-1 (acidic FGF) and FGF-2 (basic FGF), the first family members to be identified, purified, and sequenced, are widely expressed and are potent mitogens for a variety of cell types (4, 5). The gene encoding FGF-3 is a common target for activation by the mouse mammary tumor virus (6), and the genes encoding FGF-4, have transforming activity when introduced into NIH 3T3 cells (7-9). FGF-7, FGF-8, and FGF-9 are mitogens for keratinocytes, mammary carcinoma cells, and astrocytes, respectively (10-12). Recent experiments indicate that several FGFs have bioactivities that were not evident during their initial identification. For example, FGF-2 can induce ventral mesoderm in Xenopus embryos (13,14), FGF-4 is involved in growth and patterning of the chicken limb bud (15), FGF-5 controls hair follicle cycling in the mouse (16), and FGF-8 can cause duplications of the embryonic chicken midbrain (17).The nine known FGFs are between 155 and 268 amino acid residues in length and share a conserved central region of -140 amino acids. This region forms a compact (3-barrel with 3-fold symmetry that is nearly identical in structure to the folded core of interleukins-la and -13 (18-21). FGF-1 and FGF-2 also resemble interleukin-1,B in lacking a classical signal sequence. Current data indicate that FGF-1 and FGF-2 are released from cells by a route that is distinct from the endoplasmic reticulum-Golgi secretory pathway (22, 23).FGF signaling is generally assumed to occur by activation of transmembrane tyrosine kinase receptors. Four FGF receptor (FGFR) genes have been identified thus far (24), and activating or inactivating receptor mutations have been described for a subset of these genes in both mice and humans. In the mouse, disruption of the FGFR1 or FGFR2 genes leads to early embryonic lethality (25,26), and disruption of FGFR3 leads to bone overgrowth (27,28). In humans, point mutations in FGFR1, FGFR2, and FGFR3 have been found in a variety of skeletal disorders (reviewed in ref. 29).In this paper we report the identification and characterization of four new mem...

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