Scientist , Vision , Ottawa Hospital Research Institute

Assistant Professor, Department of Ophthalmology, University of Ottawa

Assistant Professor, Department of Cellular and Molecular Medicine, University of Ottawa

Research Interests

Biographical Sketch

Dr. Mears received his Ph.D in Genetics in the laboratory of Dr. Heather McDermid at the University of Alberta, Edmonton. In his thesis work he studied the molecular basis of a rare condition called cat eye syndrome which is associated with developmental anomalies including a slit-like pupil resulting from malformation of the eye.

From there he joined the laboratory of Dr. Michael Walter (University of Alberta) where he studied glaucoma. This work led to the identification of a transcription factor which is critical for normal development of the anterior chamber of the eye. In 1998 he joined the laboratory of Dr. Anand Swaroop at the University of Michigan. He continued his interest in ocular transcription factors but now turned his attention to the retina. His studies involved several projects including genetic analysis of families with retinal diseases and investigating the roles of retinal transcription factors in development and function of the photoreceptors. He discovered that the transcription factor Nrl is essential for the normal development of the rod photoreceptors, the neurons essential for vision under conditions of low ambient light (i.e night-vision). Dr. Mears joined the Research Institute in June 2003.

Major Research Activities

The photoreceptors of the retina contain the light sensitive pigments or opsins which are necessary to initiate the visual process. There are two basic types of these neurons. The rods are highly sensitive and provide low acuity vision under conditions of low ambient light. In contrast, the cones are less sensitive but are responsible for high acuity vision under bright light conditions. There are also different sub-types of cones which express different opsins, and their different wavelength sensitivities are the basis of the ability to see colour. In the majority of retinal diseases, it is the malfunction or death of the photoreceptors that results in the impairment or loss of vision.

At the molecular level, the role of the photoreceptors in the conversion of the light stimulus into a biochemical signal (and ultimately an electrical impulse) is well defined. Unfortunately, other molecular processes underlying the development, maintenance, and survival of photoreceptors are poorly understood. If the networks and pathways controlling these processes could be elucidated it would be possible to identify what goes wrong during disease, and more importantly what measures could be taken therapeutically to slow or prevent the loss of vision. The genetic and molecular dissection of the different types of photoreceptors is complicated and is further hindered by the fact that the rods outnumber cones 20:1, making analysis of cones problematic at best. The mouse is an excellent model system for studying the retina, but like humans, rods are predominant in their retina. However, by deleting a rod photoreceptor-specific transcription factor Nrl in mouse, I generated a mouse strain that only has cone photoreceptors. This animal presents us with an unrivalled opportunity to study the photoreceptors. The transcripts of genes that are known to be preferentially (or exclusively) expressed in rods are now undetectable in the retina of these mice, whereas, cone-enriched transcripts, which may have been barely detectable before are highly expressed. A second transcription factor, the cone-rod homeobox (Crx) is known to regulate many genes in both rods and cones. When Crx is deleted in mice, the photoreceptors fail to develop and function appropriately. Nrl and Crx are known to be integrally linked and in some cases actually coordinate gene expression together.

The major project in my laboratory is to elucidate the photoreceptor regulatory networks that are responsible for normal development and function of these neurons. Using a genomics approach and studying the global expression profiles of the retina of the Nrl, Crx and other strains of mice with developmental defects that impact the photoreceptors, it is possible to generate significant information on the molecular basis of these processes and to determine the specific roles of the different transcription factors. This information will provide considerable insight into the mechanisms of disease and may lead to the development of therapeutic strategies to combat these devastating diseases that lead to visual impairment or blindness.

Major Awards

Canadian Foundation for Innovation, New Opportunities Grant 2003
Tier 2 Canada Research Chair 2004-2009

Current Grant Support

Selected Publications

Yu, J., He, S., Friedman, J.S., Akimoto, M., Ghosh, D., Mears, A.J., Hicks, D., Swaroop, A. (2004). Altered expression of genes of the Bmp/Smad and Wnt/Calcium signaling pathways in the cone-only Nrl-/- mouse retina, revealed by gene profiling using custom cDNA microarrays. Journal of Biological Chemistry, 279: 42211-42220. PubMed ID: 15292180

Strettoi, E., Mears, A.J., Swaroop, A. (2004). Recruitment of the rod pathway by cones in the absence of rods. Journal of Neuroscience, 24: 7576-7582. PubMed ID: 15329405

Yoshida, S.*, Mears, A.J.*, Friedman, J.S., Carter, T., He, S., Oh, E., Jing, Y., Farjo, R., Fleury, G., Barlow, C., Hero, A.O., Swaroop, A. (2004). Expression profiling of the developing and mature Nrl-/- mouse retina: Identification of retinal disease candidates and transcriptional regulatory targets of Nrl. Human Molecular Genetics, 13: 1487-1503. PubMed ID: 15163632

Mears, A.J., Kondo, M., Swain, P.K., Takada, Y., Bush, R.A., Saunders, T.L., Sieving, P.A., Swaroop, A. (2001). Nrl is required for the development of rod photoreceptors. Nature Genetics, 29:447-452. PubMed ID: 11694879

Mears, A.J., Hiriyanna, S., Vervoort, R., Yashar, B., Gieser, L., Fahrner, S., Daiger, S.P., Heckenlively, J.R., Sieving, P.A., Wright, A.F., Swaroop, A. (2000). Remapping of the RP15 locus for X-linked cone-rod degeneration to Xp11.4-p21.1, and identification of a de novo insertion in the RPGR exon ORF15. American Journal of Human Genetics, 67:1000-1003. PubMed ID: 10970770

Laboratory Members

Postdoctoral Fellows

Melanie Lalonde

Technicians

Jennifer Kreiger