Lhx2 Determines Odorant Receptor Expression Frequency in Mature Olfactory Sensory Neurons

Abstract

A developmental program of epigenetic repression prepares each mammalian olfactory sensory neuron (OSN) to strongly express one allele from just one of hundreds of odorant receptor (OR) genes, but what completes this process of OR gene choice by driving the expression of this allele is incompletely understood. Conditional deletion experiments in mice demonstrate that Lhx2 is necessary for normal expression frequencies of nearly all ORs and all trace amine-associated receptors, irrespective of whether the deletion of Lhx2 is initiated in immature or mature OSNs. Given previous evidence that Lhx2 binds OR gene control elements, these findings indicate that Lhx2 is directly involved in driving OR expression. The data also support the conclusion that OR expression is necessary to allow immature OSNs to complete differentiation and become mature. In contrast to the robust effects of conditional deletion of Lhx2, the loss of Emx2 has much smaller effects and more often causes increased expression frequencies. Lhx2:Emx2 double mutants show opposing effects on Olfr15 expression that reveal independent effects of these two transcription factors. While Lhx2 is necessary for OR expression that supports OR gene choice, Emx2 can act differently; perhaps by helping to control the availability of OR genes for expression.

Cooperative interactions enable singular olfactory receptor expression in mouse olfactory neurons

“…RNA-seq of the FAC-sorted cells verifies the deletion of the floxed exons in mOSNs and the generation of a mutant Lhx2 mRNA that does not encode for Lhx2 protein ( Figure 4—figure supplement 1 ). Lhx2 gene deletion results in significant downregulation of OR gene expression ( Figure 4B ), a result consistent with the partial deletion of a different floxed Lhx2 allele from mOSNs ( Zhang et al, 2016 ). Furthermore, upon Lhx2 deletion the Lhx2 ChIP-seq signal is depleted genome-wide and from the Greek Islands ( Figure 4C,D ).…”

Cooperative interactions enable singular olfactory receptor expression

“…Lhx2 gene deletion results in significant downregulation of OR gene expression ( Figure 4B), a result consistent 00 with the partial deletion of a different floxed Lhx2 allele from mOSNs (Zhang et al, 2016). Furthermore, upon 01…”

The Transcriptional Logic of Mammalian Neuronal Diversity

“…For example, Foxg1 , which split forebrain from other cell types, is known to be critically required for normal development of the telencephalon ( Xuan et al, 1995 ; Danesin and Houart, 2012 ) and is known to function cell autonomously within the olfactory placode for the production of olfactory sensory neurons, as well as for all other cells in the olfactory lineage ( Duggan et al, 2008 ). Similarly, at the next levels, Tbr1 ( Bedogni et al, 2010), Satb2 Leone et al (2014) , Egr3 ( Chandra et al, 2015 ), Isl1 ( Lu et al, 2013 ) and Emx2 ( Zhang et al, 2016 ), are known as KTRs involved in the development and/or maintenance of the relevant cell types, providing significant validation of this method.…”