Roderick McInnes, MD, PhD
Developmental & Stem Cell Biology
University of Toronto
University of Toronto
Holder of Anne and Max Tannenbaum Chair
Canadian Institutes of Health Research
Institute of Genetics
- BSc (Honours), Department of Biology, Dalhousie University, Halifax, NS (1965)
- MD (Distinction), Dalhousie University Medical School (1970)
- Fellowship (Paediatrics), Royal College of Physicians and Surgeons (Canada) (1977)
- PhD, Department of Biology, McGill University, Montreal, Quebec (1978)
Our research examines three important problems:
- The regulation of eye development. We discovered the vertebrate homeobox gene Chx10, and showed that it is essential for eye development. We then identified the dChx1 and dChx2 genes in flies, and demonstrated that they are functional orthologues of Chx10, which will allow us to take advantage of the power of fly genetics to identify the regulatory pathways in which these genes (and by implication, vertebrate Chx10) are situated. More recently, we identified the transcription factor Prdm8, and found that it is required for the maintenance of a major class of retinal interneurons, rod bipolar cells. Our current goal is to place Prdm8 within the network of genes that control retinal interneuron formation.
- The biochemical mechanisms underlying inherited photoreceptor degeneration (IPD). We identified a novel principle – the one hit or constant risk model - that underlies the death of photoreceptors in IPDs. We found that the presence of a mutant photoreceptor gene places the cells at a constant risk of death. Our current goal is to identify the biochemical changes in the mutant retina that underlie the constant risk. Most significantly, we established that a massive (15-30 fold) increase in the vasoactive peptide endothelin 2 occurs in mutant photoreceptors, in the presence of a mutation in virtually any photoreceptor gene. Ablation of endothelin 2 function in mouse models of IPD leads to a 45% reduction in cell death, one of the largest rescue effects ever seen. We now wish to identify the downstream events that lead to this rescue, a finding with clinical implications.
- The genetics of the synapse and axon guidance. We discovered a novel CUB domain transmembrane protein, Neto1, and demonstrated that it is a critical component of the NMDA receptor (NMDAR) protein complex at the synapse: Neto1 is required for normal NMDAR-dependent hippocampal synaptic plasticity, spatial learning and memory. Remarkably, we also found that the deficits in synaptic plasticity, learning and memory in Neto1-null mice are rescued by the ampakine CX546, at doses without effect in wild type. These results demonstrate that an inherited learning defect can be pharmacologically rescued, a finding with therapeutic implications for humans. We are now investigating the role of a related protein, Neto2, at the synapse, and the roles of both Neto proteins in axon guidance, since mice lacking either protein have profound axon guidance defects in the developing spinal cord.
Ferda Percin E, Ploder LA, Yu JJ, Arici K, Horsford DJ, Rutherford A, Bapat B, Cox DW, Duncan AM, Kalnins VI, Kocak-Altintas A, Sowden JC, Traboulsi E, Sarfarazi M, McInnes RR. (2000). Human microphthalmia associated with mutations in the retinal homeobox gene CHX10. Nature Genetics 25, 397-401.
Clarke G, Collins RA, Leavitt BR, Andrews DF, Hayden MR, Lumsden CJ, McInnes RR. (2000). A one-hit model of cell death in inherited neuronal degeneration. Nature 406, 195-199.
Clarke G, Goldberg AF, Vidgen D, Collins L, Ploder L, Schwarz L, Molday LL, Rossant J, Szél A, Molday RS, Birch DG, McInnes RR. (2000). Rom-1 is required for rod photoreceptor viability and disk morphogenesis. Nature Genetics 25, 67-73.
Freund CL, Gregory-Evans CY, Furukawa T, Papaioannou M, Looser J, Ploder L, Bellingham J, Ng D, Herbrick JA, Duncan A, Scherer SW, Tsui LC, Loutradis-Anagnostou A, Jacobson SG, Cepko CL, Bhattacharya SS, McInnes RR. (1997). Cone-rod dystrophy due to mutations in a novel photoreceptor-specific homeobox gene (CRX) essential for maintenance of the photoreceptor. Cell 91, 543-553.
Burmeister M, Novak J, Liang MY, Basu S, Ploder L, Hawes NL, Vidgen D, Hoover F, Goldman D, Kalnins VI, Roderick TH, Taylor BA, Hankin MH, McInnes RR. (1996). Ocular retardation mouse caused by Chx10 homeobox null allele: impaired retinal progenitor proliferation and bipolar cell differentiation. Nature Genetics 12, 376-384.
Pharmaceuticals Containing Retinal Stem Cells