David Lohnes, Ph.D.

Professor and Interim Chair

Degrees

B.Sc. Biochemistry (Honours), Queen's University, Kingston, Ontario, Canada (1984).
Ph.D. Biochemistry (Dr. Glen Jones), Queen's University, Kingston, Ontario, Canada (1989).
Postdoctoral Fellow, CNRS/LGME Strasbourg, France (1989-1994)

Contact info:

RGN, Rm. 3510C Phone: 562-5800 x8684 Email: dlohnes@uottawa.ca

Research Interests:

Work in our laboratory focuses on two general themes: (i) the roles of retinoids as anti-cancer agents in the skin and: (ii) the molecular mechanisms involved in patterning of the embryonic axis.

Theme 1; Retinoids as anti-cancer agents. The active form of vitamin A, retinoic acid, signals through a family of nuclear receptors, the RARs. Work spanning several decades has shown that retinoids, such as retinoic acid, can suppress certain forms of epithelial cancers such as epidermal squamous cell carcinoma. However, the mechanism by which retinoids exert this anti-tumorigenic effect, and the role of each of the three RARs in this process, are relatively unknown. We have used a panel of RAR "knockout" mice to explore the specific role of each of these receptors in conveying the anti-cancer effects of retinoic acid in the skin. Using this model system, we have found that one of these receptors, RAR , specifically mediates these tumor-suppressive effects. Keratinocytes lacking RAR are predisposed to form tumors following oncogenic transformation with Ras, and these knockout cells no longer respond to retinoic acid in terms of growth arrest and apoptosis. We have now used this model to isolate RAR target genes which may play a role in this cancer model, and are presently exploring several promising candidates. In parallel studies, we are performing a molecular dissection of RAR to attempt to understand which of its functions are involved in transducing these anti-cancer effects.

Theme 2; Patterning the embryonic axis. In the early vertebrate embryo, information is imparted which results in proper patterning along the main (anterior-posterior) body axis. This information typically impacts on expression of a family of transcription factors, the Hox genes, which are essential for this patterning process. However, the means by which Hox genes are regulated is incompletely understood. A number of factors, including retinoic acid, fibroblast growth factor and Wnts signaling molecules, have been implicated in anterior-posterior patterning. Our recent work has shown that two of these pathways, retinoic acid and wnt, regulate the expression of a gene, Cdx1, the product of which is subsequently required for proper regulation of Hox expression.

The Cdx family (Cdx1, Cdx2 and Cdx4) encode homeodomain transcription factors. During development, all three Cdx genes are expressed in overlapping domains in the posterior embryo, and there is ample evidence that the Cdx proteins are direct regulators of Hox expression. Moreover, Cdx1 and Cdx2 are also expressed in hindgut endoderm and in colon epithelium, and Cdx2 heterozygotes exhibit intestinal metaplasia suggestive of a role in endodermal patterning.

A major objective of our group is to better understand the roles of the Cdx members in axial and endoderm pattering. Work to this end focuses on understanding the pathways governing the expression of Cdx genes, as well as the identification and characterization of transcriptional co-factors necessary for Cdx-mediated transcription. Finally, Cdx2 homozygous null mutants die during the peri-implantation period and Cdx4 null mutants have not yet been reported. To better understand the role of these Cdx members, we are generating and characterizing novel Cdx mouse mutants.

Selected publications.

M. Béland, N. Pilon, J.R. Sylvestre, M. Houle, P. Prinos and D. Lohnes (2004). Cdx1 and LEF/TCF interact genetically and physically. Mol. Cell. Biol. 24, 5028-5038.
C.F. Chen, P. Goyette and D. Lohnes (2004). RAR acts as a Tumor Suppressor in Keratinocytes. Oncogene, 23, 5350-5359.
M. Houle, J.R. Sylvestre and D. Lohnes (2003). RA is a critical regulator of Cdx1 in vivo. Development 130 (26), 6555-6567.
D. Lohnes (2003). The Cdx1 homeodomain protein: an integrator of posterior signaling in the mouse. BioEssays, 25, 971-980.
P. Prinos, S. Joseph, K. Oh, B. Meyer, P. Gruss and D. Lohnes (2001). Multiple pathways govern Cdx1 expression during murine development. Dev. Biol. 239, 257-269.
D. Allan, M. Houle, N. Bouchard, B. I. Meyer, P. Gruss and D. Lohnes (2001). RAR and Cdx1 act synergistically in vertebral patterning. Dev. Biol. 240, 46-60.
P. Goyette, D. Allan, P. Peschard, C.F. Chen, W. Wang and D. Lohnes (2000). Regulation of Gli activity by all-trans retinoic acid in mouse keratinocytes. Cancer Research 60, 5386-5389.
M. Houle, P. Prinos, A. Iulianella, N. Bouchard and D. Lohnes (2000). Cdx1 is a Direct Retinoic Acid Receptor Target Gene; A New Pathway for Retinoids and Vertebral Specification. Mol. Cell Biol. 20, 6579-6586.
P. Goyette, C.F. Chen, W. Wang, F. Seguin and D. Lohnes (2000). Characterisation of retinoic acid receptor (RAR)-deficient keratinocytes. J. Biol. Chem. 275, 16497-16505.