Touch receptor end-organ innervation and function requires sensory neuron expression of the transcription factor Meis2

Abstract

Touch sensation is primarily encoded by mechanoreceptors, sometimes called Low-Threshold Mechanoreceptors (LTMRs), with their cell bodies in the Dorsal Root Ganglia (DRG). LTMRs make up no more that 20% of all sensory neurons and exhibit great diversity in terms of molecular signature, terminal ending morphology and electrophysiological properties, mirroring the complexity of tactile experience. LTMRs are an interesting model to study the molecular cues controlling neuronal diversification in terms of both molecular specification and target-field innervation. The morphological specialization of the sensory end-organ of LTMRs exhibits striking diversity between different mechanoreceptor types and whether it occurs in the glabrous or hairy skin. Much has been learnt about transcriptional codes that define different LTMR subtypes, but the identification of molecular players that participate in their late maturation has not been extensively addressed. Here we identified the TALE homeodomain transcription factor Meis2 as a key regulator of LTMR targetfield innervation. Meis2 is specifically expressed in cutaneous LTMRs and its expression depends on target-derived signals. Meis2 gene inactivation in mouse sensory neurons precursors or early postmitotic neurons allows normal survival and specification of LTMRs. However, LTMRs lacking Meis2 show pronounced defects in end-organ innervation which was accompanied by severely impaired receptor properties and behavioral responses. These results establish Meis2 as a major transcriptional regulator controlling the orderly formation of peripheral end-organs required for touch.

The autism-associated Meis2 gene is necessary for cardiac baroreflex regulation in mice

“…In our mouse model, we could not evidence any neuronal loss of vagal neurons of the JNG, suggesting that Meis2 inactivation does not affect neuronal survival or identity as demonstrated by the normal expression of Ntrk2, Ntrk3 and Ret. These results are in line with our previous studies on Meis1 or Meis2 inactivation in different types of peripheral neurons 31,36 . When Meis1 is specifically inactivated in sympathetic neurons, distal innervation of target organs, including the heart, is compromised, but early sympathetic specification is unaffected 31 .…”

“…More recently, we found that Meis2 inactivation in postmitotic peripheral sensory neurons dictates comparable phenotypes for DRG touch neurons with incomplete distal innervation, impaired electrophysiological responses to mechanical stimuli and reduced touch sensation 36 . In the present study, because Meis2 is essential for normal heart development, we took advantage of the same mouse strain as used previously to investigate, independently of cardiac malformations, if Meis2 targeted inactivation in peripheral sensory neurons also recapitulates some of the cardiac sympatho-vagal imbalance phenotypes reported in ASD studies.…”

“…The mouse strain used here was Isl1 +/CRE ::Meis2 LoxP/LoxP in which the 8 th homeobox-containing exon was flanked by LoxP sites 36 . Both in mouse and human, Meis2 mutations causes severe developmental anomalies of the heart.…”

“…Moreover, pulse BP measurement revealed a great variability of beat-to-beat control of heart rate at baseline. We and others’ single cells RNAseq (scRNAseq) analyses have previously reported Meis2 expression in peripheral sensory neurons 36,43–46 . In spinal DRG sensory neurons, Meis2 is expressed by subclasses of mechanosensitive neurons mediating touch perception 36,43–45 , and we showed, using the Isl1 +/CRE ::Meis2 LoxP/LoxP mouse strain, that specific post-mitotic Meis2 inactivation in those neurons impaired their electro-physiological responses to mechanical stimuli and strongly altered evoked-touch perception.…”

“…We and others’ single cells RNAseq (scRNAseq) analyses have previously reported Meis2 expression in peripheral sensory neurons 36,43–46 . In spinal DRG sensory neurons, Meis2 is expressed by subclasses of mechanosensitive neurons mediating touch perception 36,43–45 , and we showed, using the Isl1 +/CRE ::Meis2 LoxP/LoxP mouse strain, that specific post-mitotic Meis2 inactivation in those neurons impaired their electro-physiological responses to mechanical stimuli and strongly altered evoked-touch perception. In a scRNAseq performed on vagal sensory neurons 46 , Meis2 expression is reported in distinct neuronal subpopulations that also express Piezo2 (Supplementary Figure 2; https://ernforsgroup.shinyapps.io/vagalsensoryneurons/), and that are molecularly similar to mechanosensitive neurons of the DRG.…”