Professor, Department of Biochemistry & Molecular Biology
Cumming School of Medicine
HMRB 406, 3330 Hospital Drive, NW
Calgary, AB T2N 4N1
Spermatogenesis represents one of the few ongoing differentiation systems for study in mammals. One problem in the study of spermatogenesis is that it cannot (yet) be recapitulated in cell culture and it is thus difficult to address functional questions: however, transgenic and knockout models are commonly used.
We cloned the spermatid-specific Odf1 gene, which encodes a 27 kD sperm tail-specific protein that is a major structural component of outer dense fibers. The function of these fibers, which surround the axoneme in the tail, is unknown. We study Odf1’s interaction with other proteins and its function in the sperm tail. We cloned several proteins that bind Odf1 using yeast 2-hybrid approaches: Odf2, a major ODF protein, Spag4, an axonemal, microtubule-binding protein, Spag5, related to the spindle protein Deepest, and KLC3, a novel kinesin light chain. KLC3 is most likely involved in the dramatic movement of mitochondria from the periphery of haploid spermatids to the midpiece of the sperm tail, a region involved in generating energy for movement. We found that interactions are mediated by leucine zipper motifs. The role of these proteins in morphogenesis and sperm function is a major focus.
Recently, it was shown that Odf2 is a component of centrioles in all somatic cells. We have generated Odf2-knockout mice to understand the roles of Odf2 in the sperm tail and in early embryonic development. In parallel, we are investigating components of primary cilia, sensory structures on most cells that originate at the basal body of the centriole. Odf2 is crucial for development of the primary cilium.
Primary cilia are present on many cells and appear to function in part as sensory organelle. Primary cilia originate from basal bodies. Abnormalities of primary cilia in human have been linked to serious disease. We demonstrated that treatment of cells with lithium (a drug commonly used to treat bipolar disorder) results in dramatic elongation of primary cilia. We recently showed that CRMP2 protein is a component of centrosomes/basal bodies in somatic cells and is crucial for development of the primary cilium. Centrosomes are normally closely associated with the nucleus. We found that hypoxia can disturb the association of centrosome and nucleus.
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