Common Promoter Elements in Odorant and Vomeronasal Receptor Genes

In mammals, odorants and pheromones are detected by hundreds of odorant receptors (ORs) and vomeronasal receptors (V1Rs and V2Rs) expressed by sensory neurons that are respectively located in the main olfactory epithelium and in the vomeronasal organ. Even though these two olfactory systems are functionally and anatomically separate, their sensory neurons show a common mechanism of receptor gene regulation: each neuron expresses a single receptor gene from a single allele. The mechanisms underlying OR and VR gene expression remain unclear. Here we investigated if OR and V1R genes share common sequences in their promoter regions

Identification of potential regulatory motifs in odorant receptor genes by analysis of promoter sequences

Mouse odorant receptors (ORs) are encoded by >1000 genes dispersed throughout the genome. Each olfactory neuron expresses one single OR gene, while the rest of the genes remain silent. The mechanisms underlying OR gene expression are poorly understood. Here, we investigated if OR genes share common cis-regulatory sequences in their promoter regions. We carried out a comprehensive analysis in which the upstream regions of a large number of OR genes were compared. First, using RLM-RACE, we generated cDNAs containing the complete 5′-untranslated regions (5′-UTRs) for a total number of 198 mouse OR genes. Then, we aligned these cDNA sequences to the mouse genome so that the 5′ structure and transcription start sites (TSSs) of the OR genes could be precisely determined. Sequences upstream of the TSSs were retrieved and browsed for common elements. We found DNA sequence motifs that are overrepresented in the promoter regions of the OR genes. Most motifs resemble O/E-like sites and are preferentially localized within 200 bp upstream of the TSSs. Finally, we show that these motifs specifically interact with proteins extracted from nuclei prepared from the olfactory epithelium, but not from brain or liver. Our results show that the OR genes share common promoter elements. The present strategy should provide information on the role played by cis-regulatory sequences in OR gene regulation

Ric-8B interacts with G alpha olf and G gamma 13 and co-localizes with G alpha olf, G beta 1 and G gamma 13 in the cilia of olfactory sensory neurons

Olfactory sensory neurons are able to detect odorants with high sensitivity and specificity. We have demonstrated that Ric-8B, a guanine nucleotide exchange factor (GEF), interacts with G alpha olf and enhances odorant receptor signaling. Here we show that Ric-8B also interacts with G gamma 13, a divergent member of the G gamma subunit family which has been implicated in taste signal transduction, and is abundantly expressed in the cilia of olfactory sensory neurons. We show that G beta 1 is the predominant GP subunit expressed in the olfactory sensory neurons. Ric-8B and G beta 1, like G alpha olf and G gamma 13, are enriched in the cilia of olfactory sensory neurons. We also show that Ric-8B interacts with G alpha olf in a nucleotide dependent manner, consistent with the role as a GEF. Our results constitute the first example of a GEF protein that interacts with two different olfactory G protein subunits and further implicate Ric-8B as a regulator of odorant signal transduction. (C) 2008 Elsevier Inc. All rights reserved

A transcriptome-based signature of pathological angiogenesis predicts breast cancer patient survival.

The specific genes and molecules that drive physiological angiogenesis differ from those involved in pathological angiogenesis, suggesting distinct mechanisms for these seemingly related processes. Unveiling genes and pathways preferentially associated with pathologic angiogenesis is key to understanding its mechanisms, thereby facilitating development of novel approaches to managing angiogenesis-dependent diseases. To better understand these different processes, we elucidated the transcriptome of the mouse retina in the well-accepted oxygen-induced retinopathy (OIR) model of pathological angiogenesis. We identified 153 genes changed between normal and OIR retinas, which represent a molecular signature relevant to other angiogenesis-dependent processes such as cancer. These genes robustly predict the survival of breast cancer patients, which was validated in an independent 1,000-patient test cohort (40% difference in 15-year survival; p = 2.56 x 10-21). These results suggest that the OIR model reveals key genes involved in pathological angiogenesis, and these may find important applications in stratifying tumors for treatment intensification or for angiogenesis-targeted therapies