Molecular Genetics Of Early Eye Development

National Eye Institute

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Abstract

Olfactomedin 1 (Olfm1) is a secreted glycoprotein belonging to a family of olfactomedin domain-containing proteins. Two zebrafish olfactomedin 1 genes (olfm1a and olfm1b) are expressed in developing retina and other neuronal tissues. Over-expression of full-length Olfm1, as well as C-terminally truncated forms increased the thickness of the optic nerve and facilitated its branching in the optic tectum, while injection of morpholino oligonucleotides against olfm1 reduced eye size and inhibited optic nerve extension in the developing zebrafish. To study functions of Olfm1, we produced several PC12 cell lines stably transfected with Olfm1. PC12-expressing cells formed short neurite-like structures in about 40% of cells and longer neurites in about 3% of cells. Upon stimulation with nerve growth factor, Olfm1-expressing cells produced more neurites per cell than control cells and individual neurites formed more branching points in Olfm1-expressing cells (3.3 0.2) than individual neurites in control PC12 cells (1.4 0.2). Addition of conditioned medium from Olfm1-expressing cells or purified Olfm1 protein but not conditioned medium from control PC12 cells induced formation of stress fibers in NIH3T3 cells. Formation of stress fibers could be inhibited by inhibitors of Wnt signaling sFRP1, WIF-1 or Dkk1. Olfm1 interacts with several frizzled receptors as was shown by immunoprecipitation experiments and by binding of Olfm1 to the surface of cells expressing cysteine-rich domains of different sFRPs and Frizzled proteins. These data together with our previous observations about interaction of Olfm1 and WIF-1 show that Olfm1 interacts with structurally unrelated components of Wnt signaling pathway containing the WIF or cysteine-rich domains. We suggest that Olfm1 may modulate Wnt signaling pathway by interaction with its components in neuronal tissues, the preferential sites of Olfm1 expression.