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Retinal ganglion cells form orderly topographic connections with the tectum, establishing a continuous neural representation of visual space. Mapping along the dorsal--ventral axis requires interactions between EphB and ephrin-B cell-surface molecules expressed as countergradients in both retina and tectum. We have discovered that the diffusible TGF [beta]-related factor Radar (Gdf6a) is necessary and sufficient for activation of dorsal markers, such as Bmp4, Tbx5, Tbx2b, and Ephrin-B2, and suppression of the ventral marker Vax2 in the zebrafish retina. Radar mutant axons innervate only the dorsal half of the tectum, where they form a compressed retinotectal map. Wild-type cells transplanted into the dorsal retina are able to rescue the dorsal identity of nearby mutant cells. Moreover, Radar overexpression 'dorsalizes' retinal ganglion cell identity in the ventral retina. We conclude that Radar is near the top of a signaling cascade that establishes dorsal--ventral positional information in the retina and controls the formation of the retinotectal map. patterning | eye development | ocular coloboma | bone morphogenetic protein | rectum

Human colonic epithelial cell renewal, proliferation, and differentiation are stringently controlled by numerous regulatory pathways. To identify genetic programs of human colonic epithelial cell differentiation in vivo as well as candidate marker genes that define colonic epithelial stem/progenitor cells and the stem cell niche, we applied gene expression analysis of normal human colon tops and basal crypts by using expression microarrays with 30,000 genes. Nine hundred and sixty-nine cDNA clones were found to be differentially expressed between human colon crypts and tops. Pathway analysis revealed the differential expression of genes involved in cell cycle maintenance and apoptosis, as well as genes in bone morphogenetic protein (BMP), Notch, Wnt, EPH, and MYC signaling pathways. BMP antagonists gremlin 1, gremlin 2, and chordin-like 1 were found to be expressed by colon crypts. In situ hybridization and RT-PCR confirmed that these BMP antagonists are expressed by intestinal cryptal myofibroblasts and smooth muscle cells at the colon crypt. In vitro analysis demonstrated that gremlin 1 partially inhibits Caco-2 cell differentiation upon confluence and activates Wnt signaling in normal rat intestinal epithelial cells. Collectively, the expression data set provides a comprehensive picture of human colonic epithelial cell differentiation. Our study also suggests that BMP antagonists are candidate signaling components that make up the intestinal epithelial stem cell niche. gremlin | expression profiling microarray | crypt maturation program | myofibroblast

Ewes from the Booroola strain of Australian Merino sheep are characterized by high ovulation rate and litter size. This phenotype is due to the action of the [FecB.sup.B] allele of a major gene named FecB, as determined by statistical analysis of phenotypic data. By genetic analysis of 31 informative half-sib families from heterozygous sires, we showed that the FecB locus is situated in the region of ovine chromosome 6 corresponding to the human chromosome 4q22-23 that contains the bone morphogenetic protein receptor IB (BMPR-IB) gene encoding a member of the transforming growth factor-[Beta] (TGF-[Beta]) receptor family. A nonconservative substitution (Q249R) in the BMPR-IB coding sequence was found to be associated fully with the hyperprolificacy phenotype of Booroola ewes. In vitro, ovarian granulosa cells from [FecB.sup.B]/[FecB.sup.B] ewes were less responsive than granulosa cells from [FecB.sup.+]/[FecB.sup.+] ewes to the inhibitory effect on steroidogenesis of GDF-5 and BMP-4, natural ligands of BMPR-IB. It is suggested that in [FecB.sup.B]/[FecB.sup.B] ewes, BMPR-IB would be inactivated partially, leading to an advanced differentiation of granulosa cells and an advanced maturation of ovulatory follicles.