Odorant receptor gene choice and axonal wiring in mice with deletion mutations in the odorant receptor gene SR1

Abstract:

In the mouse, a mature olfactory sensory neuron (OSN) of the main olfactory epithelium (MOE) expresses one allele of one of the 1200 odorant receptor (OR) genes in the genome. The mechanisms that underlie the one receptor–one neuron rule remain poorly understood. A popular experimental paradigm for OR gene choice is to delete an OR coding region by gene targeting or in a transgene. Here we have applied this ∆OR paradigm to SR1, also known as MOR256-3 or Olfr124. This gene is expressed in OSNs of the MOE, and in ~ 50% of the OSNs of the septal organ. In heterozygous ∆SR1 mice, we observe an unprecedented biallelic expression rate of 30% at the SR1 locus. In homozygous ∆SR1 mice, we find a significant increase in the number of septal organ OSNs that undergo apoptosis. As a population, ∆SR1 OSNs project their axons to 81–85 glomeruli in each half of the OB, and coexpress at least 77 OR genes as evaluated by single-cell molecular analysis. There are no obvious or simple rules for the set of OR genes that are coexpressed with the ∆SR1 allele. The frequencies of coexpression are different for ∆SR1 OSNs in the septal organ compared to those in the MOE. We propose that there are as many as five scenarios for the fate of individual ∆SR1 OSNs.

My comment: All scenarios for the fate of olfactory sensory neurons are nutrient-dependent and RNA-mediated in the context of the physiology of reproduction.

In the same issue of this journal, see:

RNA-mediated toxicity in neurodegenerative disease

Abstract excerpt (September 2013):

As part of the special issue on RNA and Splicing Regulation in Neurodegeneration, this review intends to explore the diverse RNA-related mechanisms contributing to neurodegeneration, with a special emphasis on findings emerging from animal models.

See also the other articles that link RNA-mediated events to cell type differentiation and the Special Section: RNA and splicing regulation in neurodegeneration

Regulation of gene expression in mammalian nervous system through alternative pre-mRNA splicing coupled with RNA quality control mechanisms

Abstract

Eukaryotic gene expression is orchestrated on a genome-wide scale through several post-transcriptional mechanisms. Of these, alternative pre-mRNA splicing expands the proteome diversity and modulates mRNA stability through downstream RNA quality control (QC) pathways including nonsense-mediated decay (NMD) of mRNAs containing premature termination codons and nuclear retention and elimination (NRE) of intron-containing transcripts. Although originally identified as mechanisms for eliminating aberrant transcripts, a growing body of evidence suggests that NMD and NRE coupled with deliberate changes in pre-mRNA splicing patterns are also used in a number of biological contexts for deterministic control of gene expression. Here we review recent studies elucidating molecular mechanisms and biological significance of these gene regulation strategies with a specific focus on their roles in nervous system development and physiology.

CLIPing the brain: Studies of protein–RNA interactions important for neurodegenerative disorders

Abstract (Open Access):

The fate of an mRNA is largely determined by its interactions with RNA binding proteins (RBPs). Post-transcriptional processing, RNA stability, localisation and translation are some of the events regulated by the plethora of RBPs present within cells. Mutations in various RBPs cause several diseases of the central nervous system, including frontotemporal lobar degeneration, amyotrophic lateral sclerosis and fragile X syndrome. Here we review the studies that integrated UV-induced cross-linked immunoprecipitation (CLIP) with other genome-wide methods to comprehensively characterise the function of diverse RBPs in the brain. We discuss the technical challenges of these studies and review the strategies that can be used to reliably identify the RNAs bound and regulated by an RBP. We conclude by highlighting how CLIP and related techniques have been instrumental in addressing the role of RBPs in neurologic diseases. This article is part of a Special Issue entitled: RNA and splicing regulation in neurodegeneration.

Heterogeneous nuclear ribonucleoprotein A1 in health and neurodegenerative disease: From structural insights to post-transcriptional regulatory roles

ELAV proteins along evolution: Back to the nucleus?

CUG-BP, Elav-like family (CELF)-mediated alternative splicing regulation in the brain during health and disease

TDP-43 high throughput screening analyses in neurodegeneration: Advantages and pitfalls

Fused in sarcoma (FUS): An oncogene goes awry in neurodegeneration

See also: JBC Thematic Minireview Series

RNA-mediated Regulation and Noncoding RNAs

Description:

A special collection of articles recently published in the Journal of Biological Chemistry under the heading of “RNA-Mediated Regulation and Noncoding RNAs” was assembled and distributed to 750 enthusiastic participants of the RNA-themed symposia at ASBMB 2008. The compendium, an ASBMB production sponsored by Cadmus Communications, highlights some of the outstanding contributions made by JBC authors to elucidating molecular mechanisms of RNA-mediated regulation by noncoding RNAs.

Ten research articles in the collection cover topics ranging from mechanisms of post-transcriptional gene regulation by microRNAs to activation of the RNA-dependent protein kinase, PKR, by double-stranded viral RNA in a process critical to the innate immune response. Additional results of recent investigations of microRNA biogenesis and mechanism of action are distilled in a minireview with a specific emphasis on the roles of microRNAs in viral infection and oncogenesis. These articles were chosen to complement symposia presentations in the “Small RNAs and Dynamic RNA Elements” sessions co-organized by Frank Slack (Yale University) and Robert Batey (University of Colorado, Boulder) and illustrate the significant advances achieved by JBC authors in understanding mechanisms of biological regulation by noncoding RNAs.

For example: An E2F/miR-20a Autoregulatory Feedback Loop (2006)

Excerpt:

Recently, a new level of regulation of E2Fs has been identified, where micro-RNAs (miRNAs) from the mir-17–92 cluster influence the translation of the E2F1 mRNA.

My comment: Why hasn’t accurate information been disseminated about the role of nutrient-dependent microRNAs in maintaining the microRNA/mRNA balance in the context of the physiology of reproduction and cell type differentiation?

See also: Feedback loops link odor and pheromone signaling with reproduction

For an example of ignorance displayed by researchers who should know that the de novo creation of olfactory receptor genes is nutrient energy-dependent see:

Cloud-based simulations on Google Exacycle reveal ligand modulation of GPCR activation pathways.

Co-author D.E. Konerding took issue with my comments about vitamin supplements and horizontal gene transfer before taking the time to learn that RNA-mediated cell type differentiation starts with the de novo creation of GPCRs. To biophysicists like Konerding, ligand modulation of GPCR activation occurs only in simulations. They cannot link their simulations to biophysically constrained cell type differentiation with mathematical models, but they also seem unwilling to admit that gene activation does not magically occur.

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