Many transmembrane proteins mediate cell-cell interactions and thereby regulate key developmental processes. Teneurins are a unique family of type II transmembrane proteins conserved from Drosophila melanogaster and Caenorhabditis elegans to vertebrates, where four paralogues exist called teneurin 1-4 . This protein class was discovered in a screen for the Drosophila homologue of the extracellular matrix protein tenascin-C . Structure and domain architecture are highly conserved across phyla. All proteins of the teneurin family share a large extracellular domain with eight tenascin-type EGF-like repeats followed by a region of conserved cysteines and YD repeats . Recently, several publications suggested that the C-terminal parts of the teneurin proteins contain peptides with similarities to corticotrophin-releasing factor (CRF) and might have a function in modulating CRF-mediated behavior . All vertebrate teneurins have an N-terminal intracellular domain with two polyproline motifs, EF-hand-like metal ion binding sites and several putative phosphorylation sites. This intracellular domain was shown to be cleaved from the membrane and translocates into the nucleus where it can interact with transcription factors and alter gene expression [5–7].
In C. elegans, RNAi knockdown and deletion of its single teneurin gene (Ten-1) results in a broad range of phenotypes, including defects in axon guidance and neuronal pathfinding, as well as gonadal disintegration and protrusion of the vulva [8–10]. Drosophila harbors two teneurin genes, Ten-a  and Ten-m/Odz [11, 12]. Mutations in either of these genes result in embryonic lethality and Ten-a mutants enhance the segmentation phenotype of weak alleles of Ten-m/Odz . It was also shown that teneurin expression is required for the proliferation and cellular identity in the Drosophila eye . Extensive localization studies in mouse [15–17] and chicken [5, 18–20] embryos, as well as in rat  and zebrafish  revealed that the different members of the teneurin protein family are expressed with overlapping patterns by distinct subpopulations of neurons. Experiments in vitro and in vivo showed that the different members of the teneurin family form disulfide-linked dimers [16, 23] and promote homophilic cell-cell adhesions and neurite outgrowth [18, 24]. These functions of the protein are believed to mediate correct pathfinding and area recognition of neurons. This was shown in the teneurin-3 knockdown mouse, which exhibits dramatic changes in the mapping of ipsilateral retinal inputs causing mismatches in binocular mapping. This is associated with major deficits in the performance of visually mediated behavioral tasks .
Recent findings suggest an important role for the teneurin protein family in establishing cortical arealization and patterning in the developing embryo. Teneurin-2 was found to be expressed in developing limbs, somites and craniofacial mesenchyme in a pattern strikingly similar to that of fibroblast growth factor 8 (Fgf8) and Fgf8 coated beads implanted into chicken limb buds induced ectopic teneurin-2 expression in situ . Furthermore, teneurin-4 transcripts are down regulated, and the expression patterns of teneurins are shifted in the cortices of mice deficient in Emx2 . These findings link the regulation of teneurin expression to Fgf8 and Emx2, two proteins that are part of a complex network of growth and transcription factors regulating arealization of the developing brain, a crucial event regulating sensory perception, the control of our movements and behavior (reviewed in ). The best studied protein in this network is Emx2. Emx2 is the vertebrate homologue of the Drosophila empty spiracles (ems) protein, which is involved in the development of the fly head . This protein is a homeobox-containing transcription factor implicated in mouse cerebral cortex development . It is expressed in a graded manner from rostral (low) to caudal (high) [30–33]. Knock-out and overexpression studies of Emx2 showed the function of this transcription factor in establishing the correct size and positioning of cortical areas [reviewed in 34]. Comparing expression analyses of different embryonic stages to the adult for both Emx2 [32, 33] and teneurins [5, 7, 35] showed that areas of Emx2 expression (e.g., the cortical plate, dentate gyrus and the olfactory bulb) strongly correlate with areas of teneurin expression, suggesting a possible role of teneurins in mediating arealization.
The human teneurin-1 gene resides on the × chromosome at position Xq25, a locus with low gene density [reviewed in 36]. Beside severe mental retardation, patients suffering from a syndrome mapped to this locus also suffer from motor sensory neuropathy, deafness and severely impaired vision [37–41]. Given the predominant expression in the developing brain and its function in establishing proper connectivity in the brain, teneurin-1 is a potential target gene for causing XLMR.
In order to provide the basis for an investigation of possible deletions and mutations in teneurin-1 of XLMR patients, we decided to delineate the gene locus and determined the transcription start site(s) of human teneurin-1. We identified a novel promoter upstream of the published transcription start, which is conserved in chicken and mice. We show that EMX2 directly binds to and regulates human teneurin-1 expression at this alternate promoter.