Abstract
The family of olfactory receptors (ORs) subserves the sense of smell and includes both functional alleles and pseudogenes, the latter identified by mutations resulting in frame shift or premature truncation. During neuronal differentiation, nonfunctional ORs are expressed initially but then are switched out, and/or the olfactory sensory neurons (OSNs) expressing them die. We carried out a transcriptomic analysis of FACS-isolated cells from ΔSox2-eGFP, Neurog1-eGFP BAC and ΔOMP-eGFP strains of uninjured and olfactory bulbectomized transgenic mice that correspond to distinct stages in the progression from globose basal cell stem cells to fully mature OSNs. We analyzed the expression pattern of 1094 unique receptors across this progression and found that the vast majority were characterized by a typical and expected pattern of expression; i.e., levels of OR mRNA peaking in mature OSNs. However, 43 ORs, including several known pseudogenes, were different, such that mRNA expression declined in the mature OSNs relative to earlier stages. Protein and promoter sequence analysis of the atypical group did not uncover any obvious differences between them and more typical ORs. Nonetheless, the pattern of expression suggests that atypical ORs may be non-functional despite the lack of any obvious abnormality in the sequence analyses.
Highlights
In addition to the spatial and epigenetic regulation of the pattern of singular, monogenic, and monoallelic expression, the functional status of olfactory receptors (ORs) controls their stabilization as they reach full maturation
The microarray analysis of gene expression during the neurogenic progression from multipotent Sox[2] (+) GBCs to the OMP (+) mature olfactory sensory neurons (OSNs) demonstrated that expression of a subset of OR genes peaks in more upstream and undifferentiated cells types as compared to the vast majority of ORs that reach a maximum in OMP (+) populations, as expected from previous analyses[24,25]
The OR genes that are characterized by an atypical pattern of expression reach a maximum in advance of full neuronal maturation and OMP expression; these atypical ORs may represent a previously unidentified population of functionally inactive genes or pseudogenes that had not been previously detected by sequence analysis[2,3]
Summary
In addition to the spatial and epigenetic regulation of the pattern of singular, monogenic, and monoallelic expression, the functional status of ORs controls their stabilization as they reach full maturation. We did observe a smaller set of ORs that exhibited an unexpected, atypical pattern of expression during the course of neuronal differentiation This set of ORs reached maximal expression in the population of eGFP-labeled GBCs and immature neurons isolated from Neurog1-eGFP BAC transgenic mice. Expression levels declined within the population of eGFP-labeled mature OSNs isolated from heterozygous ΔOMP-eGFP knock-in transgenic mice The behavior of these atypical ORs mimicked that of known pseudogenes but had not previously been classified as such and had no obvious truncations or frame-shift mutations. We characterize this set of atypical ORs here with respect to expression pattern, labeling by in situ hybridization, and analysis of gene and protein sequences by comparison with ORs whose expression are “typical” and matches expectations derived from the earlier work
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