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. Our lab previously demonstrated that Olfm1 controls optic nerve elongation during zebrafish development. As such, we were interested in determining whether this protein affects axon extension and regeneration in mammals. Overexpression of full length Olfm1 in hippocampal neurons by transient transfection increased the length of growing axons by 20%. Olfm1 also stimulated axon growth during neuronal differentiation of neural stem cells derived from the subventricular zone of adult rats. We cultured retinal explants from adult rats and demonstrated that Olfm1 increases the number and length of regenerating retinal ganglion cell axons. In vivo, Olfm1 exerts a mild neuroprotective effect on retinal ganglion cells following optic nerve crush injury, but potential effects on axon regeneration are unclear. Current efforts are focusing on optimization of Olfm1 delivery in order to gain a clearer understanding of its effects in vivo. Magnetic resonance imaging (MRI) with a 14 Tesla Bruker Avance scanner was used to analyze structural changes in the brain of mice with a deletion in the central part of the Olfm1 protein (Olfm1 KO). A three dimensional volume encompassing the whole brain was specified using three orthogonal scout images. Olfm1 KO mice are 30% smaller than their wild type littermates and relatively infertile. A similar phenotype has been described for VGF KO mice. The MRI analysis showed that the brain volume, and especially the volume of major white matter tracts located in the anterior commissure and corpus callosum as well as optic nerve, was strongly reduced in Olfm1 KO. These data suggest that Olfm1 has important functions in the regulation of neuronal differentiation and /or axonal growth in the developing and adult mammalian brain. Our previous data suggested that some olfactomedin domain-containing proteins may perform overlapping functions. We demonstrated that three proteins of this family, Olfm1, Olfm2, and Olfm3 show very similar expression patterns in the course of eye and brain development as well as in the adult eye and brain. We demonstrated that these proteins physically bind each other. Several other proteins interacting with Olfm1 and Olfm2 were also identified and the functional significance of these interactions is characterized. We produced Olfm3 knockout mice and we are in the process of producing Olfm2 knockout mice. Olfm1/Olfm3 double knockout mice have been produced and are currently under investigation.
