Identification and characterization of non-visual opsins

Up until a decade ago it was assumed that non-image forming tasks, such as the detection of light for the entrainment of the circadian timing system were performed by rod and cone photoreceptors. The identification of a third type of photosensitive cell in the ganglion cell layer of the retina containing the photopigment, melanopsin (Opn4) and several novel members of the opsin superfamily of G protein coupled receptors such as vertebrate ancient (VA) opsin and Opn3 has changed the field. A recent study has described the presence of two melanopsin genes, Opn4m and Opn4x, in non-mammalian vertebrates but only Opn4m has been described so far in mammals, which raises the question as to when the Opn4x gene was lost from their lineage. To date, the study of mammalian melanopsin has been limited to the placentals and has not included the marsupials. We isolated an Opn4m gene from the Australian marsupial, the fat-tailed dunnart, but have been unable to isolate an Opn4x gene from the fat-tailed dunnart and can find no evidence of its presence in the marsupial genome. More recent work has led to the isolation of a VA gene in both the chicken and Xenopus genomes, an unexpected finding as VA was thought to be confined to the agnatha and teleost fish. We have recently demonstrated that in chicken this photopigment is expressed within a population of hypothalamic neurones with extensive projections to the median eminence, the region of the brain containing the deep-brain photoreceptors responsible for daylength detection. Ongoing work includes the identification of two functional isoforms of Opn4 in the mouse retina, identification of three Opn4 genes in a deep sea fish, Coryphaenoides armatus and a pilot study to determine the role of Opn4 in the sleep-wake dysfunction seen in patients with schizophrenia.

Identification of candidate genes for retinal degeneration

Our understanding of inherited retinal dystrophies, a heterogeneous group of disorders, has increased substantially over the last ten years. Using the information from large scale sequencing projects in tandem with the well characterised Drosophila phototransduction pathway has enabled us to isolate genes with unknown function in the mammalian retina. One of these genes, CDS1, is currently being assessed as a candidate in human retinal dystrophies. Ongoing work also includes the identification of novel disease genes, positional cloning, and the screening of known disease genes, CYP4v2 and IMPG1, in a cohort of patients from Moorfields Eye Hospital and the Western Eye Hospital which will be extended to the Oxford Eye Hospital. A pilot study to examine the genotype/phenotype correlation in patients with diabetic macular oedema has been recently instigated.

After graduating I worked as a Clinical Biochemist in the NHS for 2 years. My research career started in the renowned group led by Professor Bob Williamson working on the identification of the gene causing Cystic Fibrosis (CF). This gave me a fantastic introduction to molecular genetics and although we missed out on identifying the gene we cloned the mouse CFTR gene and subsequent work by me enabled us to distribute a clone that was used by several groups to produce knockout mouse models of CF. My Ph.D. was on a developmental abnormality, DiGeorge Syndrome. Probes identified by me as part of the study to determine the gene/genes involved are now used routinely to diagnose the disease. My Ph.D. project and a subsequent post-doctoral position involved the isolation of genes and their subsequent characterization. I also made the construct for a knockout mouse of one of these genes, HIRA. In 1996 I moved to the Institute of Ophthalmology as a Senior Research Fellow where I initiated bioinformatics projects to utilize the data generated from the human genome project to identify novel functional retinal genes. Two of these genes have revealed the existence of pathways not previously known to be important in the mammalian retina. In 2001 I moved to Imperial College to take up a Non-Clinical Lectureship working with Professor Mark McCarthy on Type II Diabetes and continuing my interest in retinal degeneration. Since moving to Oxford in 2006, the research in my laboratory can be divided into two main areas (1) the identification of candidate genes for retinal degeneration and (2) the identification and characterization of non-visual opsins.

Publications from S.Halford

• Halford S, Bellingham J, Ocaka L, Fox M, Johnson S, Foster R G, and Hunt D M (2001) Assignment of panopsin (OPN3) to human chromosome band 1q43 by in situ hybridization and somatic cell hybrids. Cytogenet Cell Genet, 95(3-4):234-5.