The Maf-family transcription factor Nrl is a key regulator of photoreceptor differentiation in mammals. Ablation of the Nrl gene in mice leads to functional cones at the expense of rods. We show that a 2.5-kb Nrl promoter segment directs the expression of enhanced GFP specifically to rod photoreceptors and the pineal gland of transgenic mice. GFP is detected shortly after terminal cell division, corresponding to the timing of rod genesis revealed by birthdating studies. In Nrl ؊/؊ retinas, the GFP؉ photoreceptors express S-opsin, consistent with the transformation of rod precursors into cones. We report the gene profiles of freshly isolated flow-sorted GFP؉ photoreceptors from wild-type and Nrl ؊/؊ retinas at five distinct developmental stages. Our results provide a framework for establishing gene regulatory networks that lead to mature functional photoreceptors from postmitotic precursors. Differentially expressed rod and cone genes are excellent candidates for retinopathies.gene profiling ͉ gene regulation ͉ neuronal differentiation ͉ retina ͉ transcription factor E volution of higher-order sensory and behavioral functions in mammals is accompanied by increasingly complex regulation of gene expression (1). As much as 10% of the human genome is presumably dedicated to the control of transcription. Exquisitely timed expression of cell-type-specific genes, together with spatial and quantitative precision, depends on the interaction between transcriptional control machinery and extracellular signals (2, 3). Neuronal heterogeneity and functional diversity result from combinatorial and cooperative actions of regulatory proteins that form complicated yet precise transcriptional networks to generate unique gene expression profiles. A key transcription factor, combined with its cognate regulatory cis-sequence codes, specifies a particular node in the gene regulatory networks that guide differentiation and development (4).The retina offers an ideal paradigm for investigating regulatory networks underlying neuronal differentiation. The genesis of six types of neurons and Müller glia in the vertebrate retina proceeds in a predictable sequence during development (5). Subsets of multipotent retinal neuroepithelial progenitors exit the cell cycle at specific time points and acquire a particular cell fate under the influence of intrinsic genetic program and extrinsic factors (5-7). Pioneering studies using thymidine labeling and retroviral vectors established the order and birthdates of neurons in developing retina (5,(8)(9)(10)). The current model of retinal differentiation proposes that a heterogeneous pool of progenitors passes through states of competence, where it can generate a distinct subset of neurons (5). One can predict that, at the molecular level, this competence is acquired by combinatorial action of specific transcriptional regulatory proteins. Genetic ablation studies of transcription factors involved in early murine eye specification are consistent with combinatorial regulation (11-13).Rod and cone photorecep...

In developed countries, age-related macular degeneration is a common cause of blindness in the elderly. A common polymorphism, encoding the sequence variation Y402H in complement factor H (CFH), has been strongly associated with disease susceptibility. Here, we examined 84 polymorphisms in and around CFH in 726 affected individuals (including 544 unrelated individuals) and 268 unrelated controls. In this sample, 20 of these polymorphisms showed stronger association with disease susceptibility than the Y402H variant. Further, no single polymorphism could account for the contribution of the CFH locus to disease susceptibility. Instead, multiple polymorphisms defined a set of four common haplotypes (of which two were associated with disease susceptibility and two seemed to be protective) and multiple rare haplotypes (associated with increased susceptibility in aggregate). Our results suggest that there are multiple disease susceptibility alleles in the region and that noncoding CFH variants play a role in disease susceptibility.Age-related macular degeneration (AMD; OMIM 603075) is a complex degenerative disorder that primarily affects the elderly. Disease susceptibility is influenced by multiple genetic 1-5 and environmental factors 6-9 . Recently, targeted and genome-wide searches have identified alleles on chromosomes 1q and 10q that are strongly associated with disease susceptibility 10-14 . In each case, the association seems to be robust and has been replicated in multiple samples. We previously showed that the Y402H-encoding variant of CFH is strongly associated with AMD susceptibility in a sample of affected individuals and controls Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions/ Note: Supplementary information is available on the Nature Genetics website. After quality assessment of genotype data (see Methods), we tested each SNP for association in 544 unrelated affected individuals and 268 unrelated controls (Fig. 1). As expected, we observed strong association between disease status and the Y402H-encoding variant previously associated with AMD in multiple studies (likelihood ratio test χ 2 = 110.05, P <10 −25 ). Unexpectedly, 20 other variants showed even stronger association. The strongly associated SNPs fell into two linkage disequilibrium (LD) groups (colored in purple and green in Fig. 1), such that, within each group, pairwise r 2 > 0.80, and between groups, pairwise r 2 < 0.50. The Y402H-encoding variant was included in one of the LD groups (the purple group in Fig. 1). The three SNPs showing strongest association are a synonymous SNP in exon 10, rs2274700 (LRT χ 2 = 135.42, P < 10 −30 ) and two intronic SNPs, rs1410996 (LRT χ 2 = 132.70, P < 10 −29 ) and rs7535263 (LRT χ 2 = 130.43, P < 10 −29 ). We observed similar results using a family-based association test 16,17 that incorporated all 726 affected individuals genotyped. Table 1 summarizes results of family-based and case-control single-SNP association tests for rs1061170 (the Y40...

Using a large sample of cases and controls from a single center, we show that a T-->C substitution in exon 9 (Y402H) of the complement factor H gene is strongly associated with susceptibility to age-related macular degeneration, the most common cause of blindness in the elderly. Frequency of the C allele was 0.61 in cases, versus 0.34 in age-matched controls (P<1x10(-24)). Genotype frequencies also differ markedly between cases and controls (chi2=112.68 [2 degrees of freedom]; P<1x10(-24)). A multiplicative model fits the data well, and we estimate the population frequency of the high-risk C allele to be 0.39 (95% confidence interval 0.36-0.42) and the genotype relative risk to be 2.44 (95% confidence interval 2.08-2.83) for TC heterozygotes and 5.93 (95% confidence interval 4.33-8.02) for CC homozygotes.

A primary feature of age-related macular degeneration (AMD) is the presence of extracellular deposits between the retinal pigment epithelium (RPE) and underlying Bruch's membrane, leading to RPE dysfunction, photoreceptor death and severe visual loss. AMD accounts for about 50% of blind registrations in Western countries and is a common, genetically complex disorder. Very little is known regarding its molecular basis. Late-onset retinal degeneration (L-ORD) is an autosomal dominant disorder with striking clinical and pathological similarity to AMD. Here we show that L-ORD is genetically heterogeneous and that a proposed founder mutation in the CTRP5 (C1QTNF5) gene, which encodes a novel short-chain collagen, changes a highly conserved serine to arginine (Ser163Arg) in 7/14 L-ORD families and 0/1000 control individuals. The mutation occurs in the gC1q domain of CTRP5 and results in abnormal high molecular weight aggregate formation which may alter its higher-order structure and interactions. These results indicate a novel disease mechanism involving abnormal adhesion between RPE and Bruch's membrane.