Olfactomedin domain-containing proteins: possible mechanisms of action and functions in normal development and pathology

Abstract

A family of olfactomedin domain-containing proteins consists of at least 13 members in mammals. Although the first protein belonging to this family, olfactomedin, was isolated and partially characterized from frog olfactory neuroepithelim almost 20 years ago, the functions of many family members remain elusive. Most of the olfactomedin domain-containing proteins, similar to frog olfactomedin, are secreted glycoproteins that demonstrate specific expression patterns. Other family members are membrane-bound proteins that may serve as receptors. More than half of the olfactomedin domain-containing genes are expressed in neural tissues. Data obtained over the last several years demonstrate that olfactomedin domain-containing proteins play important roles in neurogenesis, neural crest formation, dorsal ventral patterning, cell-cell adhesion, cell cycle regulation, and tumorigenesis and may serve as modulators of critical signaling pathways (Wnt, bone morphogenic protein). Mutations in two genes encoding myocilin and olfactomedin 2 were implicated in glaucoma, and a growing number of evidence indicate that other genes belonging to the family of olfactomedin domain-containing proteins may contribute to different human disorders including psychiatric disorders. In this review, we summarize recent advances in understanding the possible roles of these proteins with special emphasis on the proteins that are preferentially expressed and function in neural tissues.

Fig. 1

Rooted neighbor-joining tree for the 68 full-length olfactomedin domain-containing proteins and the domain architecture of the typical human members in each subfamily. Vertical bars and Roman numerals delineate the seven subfamilies. Domain names are noted at the up right corner. Branch lengths are shown to scale. Bootstrap values based on 1000 replications are shown above the branches (Reproduced from FEBS Lett. 579 (2005) 5443-5455 [5] by permission of Dr. Wei-Jun Ma)

Fig. 2

Schematic diagram showing different forms of Olfm1 protein that produced as results of different promoter usage (exon 1 or exon 2) and alternative splicing (exon 5 or exons 6–8). The central M part of Olfm1 encoded by exons 3 and 4 are common for all forms. The olfactomedin domain is encoded by exons 7 and 8 and marked by pink color.

Fig. 3

Glaucoma-causing mutations in myocilin. More than 90% of mutations affect the olfactomedin domain. The most severe mutations (to maximum IOP higher than 40 mm Hg and mean age at diagnosis less than 30 years [71]) are marked in pink. The Arg46Stop mutation [93] that may be considered as a natural human myocilin knockout in homozygous state is marked by green color.

Fig. 4

Schematic diagram of myocilin action. Myocilin may bind Wnt antagonists WIF-1 and sFRPs and compete with Wnt for binding to several Frizzled receptors. Proteins that are affected by myocilin treatment are indicated in red. Thin uninterrupted lines with two arrows indicate proteins that interact with each other (from Kwon et al., 2009, by permission of American Society for Microbiology).

Fig. 5

The localization and proposed functions of olfactomedin domain-containing proteins in neurons. Olfactomedin domains are shown as red ovals. The N-terminal parts of olfactomedin domain-containing proteins are shown as black rectangles. Three major olfactomedin containing protein groups are expressed and function in neurons. (A) Olfm1 is mainly localized in the endoplasmic reticulum and Golgi apparatus in cell soma. It translocates to mitochondria in the event of neuronal death, forms WAVE1-Bcl-xL complex, and activates proapoptotic proteins BAX and BAK that leads to a release of cytochrome c (cytC). Secreted Olfm1 binds to a Wnt inhibitory protein, WIF1, and may serve as a modulator of Wnt signaling. Interaction of Olfm1 with unknown receptors (R) may be essential for mediating the Olfm1 action. (B) At the nodes of Ranvier, gliomedin is released from adjacent Schwann cells and binds to neurofacin (NF) and NrCAM on the axonal surface. This binding induces clustering of sodium channels and involves recruitment of ankyrin G and βIV spectrin (shown as black lines). (C) Latrophillins are seven membrane-spanning receptors localizing at the presynaptic membrane. They were identified as binding targets for spider venom, latrotoxin (Ltx), which becomes embedded into the membrane and transports calcium ions to the presynaptic body. (D) Olfm1 may also exist in presynapse and bind to β-dystrobrevin (Db), regulating the synapse attachment through the distroglycan complex. Dt; Dystrophin, St; Syntrophin, DG; alpha (a) and beta (b) Dysroglycans. The figure represents a general image of neuron. The expression of each olfactomedin protein is specific for some type of neurons in central and peripheral nervous systems.