Ontogeny of Excitatory Spinal Neurons Processing Distinct Somatic Sensory Modalities

Abstract

Spatial and temporal cues govern the genesis of a diverse array of neurons located in the dorsal spinal cord, including dI1-dI6, dIL A , and dIL B subtypes, but their physiological functions are poorly understood. Here we generated a new line of conditional knock-out (CKO) mice, in which the homeobox gene Tlx3 was removed in dI5 and dIL B cells. In these CKO mice, development of a subset of excitatory neurons located in laminae I and II was impaired, including itch-related GRPR-expressing neurons, PKC␥-expressing neurons, and neurons expressing three neuropeptide genes: somatostatin, preprotachykinin 1, and the gastrin-releasing peptide. These CKO mice displayed marked deficits in generating nocifensive motor behaviors evoked by a range of pain-related or itch-related stimuli. The mutants also failed to exhibit escape response evoked by dynamic mechanical stimuli but retained the ability to sense innocuous cooling and/or warm. Thus, our studies provide new insight into the ontogeny of spinal neurons processing distinct sensory modalities.

Making sense out of spinal cord somatosensory development

“…These excitatory interneurons are derived mainly from the dI5/dIL B lineages, which reside throughout the dorsal horn with some ventral expression (Szabo et al, 2015;Xu et al, 2008). Genetic manipulation of dI5/ dIL B neurons as a whole (via elimination of spinal cord TLX3) leads to defects in dynamic light touch, noxious thermosensation, mechanical and chemical pain, and itch, but not in motor control (Xu et al, 2013). Further dissection of dI5/dIL B lineages has shown that the RORα + subset is in part responsible for dynamic light touch, as discussed above (Bourane et al, 2015b), while noxious thermosensation appears to derive from a LMX1B + population -potentially the neurons in lamina I that contribute to the spinothalamic tract (STT) division of the ALS (Szabo et al, 2015;Todd, 2010).…”

“…The neurons that relay chemical itch signals (histaminergic and nonhistaminergic) are GRPR + and are likely dI5/dIL B derived since they reside in the superficial laminae and since conditional knockout of TLX3 causes complete elimination of GRPR in the spinal cord (Xu et al, 2013). The GRPR + neurons receive inputs from unmyelinated C-fiber sensory neurons and are selectively required for itch, as pain sensation is normal in the GRPR knockout mouse and when GRPR + neurons are ablated (Sun and Chen, 2007;Sun et al, 2009).…”

Mas and Its Related G Protein–Coupled Receptors, Mrgprs

“…They are developed from neural crest precursors in the last trimester of mouse embryogenesis and the first weeks of life (Lallemend and Ernfors, 2012). The transcription factors Runx1 and tlx3 are essential for the development of this class of neurons and directly regulate the expression of mMrgprD and mMrgprX1 starting around embryonic day 16 (Chen et al, 2006;Luo et al, 2007;Liu et al, 2008;Lopes et al, 2012;Xu et al, 2013). Runx1 also induces c-Ret in some neurons, which, in turn, switch on the expression of mMrgprA1, mMrgprA3, and mMrgprB4 in this subset of cells (Luo et al, 2007;Franck et al, 2011).…”

Dual role of Tlx3 as modulator of Prrxl1 transcription and phosphorylation

“…Ablation of Tlx3 gene affects Prrxl1 expression only at late stages of spinal cord development (from E13.5 onwards) but not at the DRG [13]. When Tlx3 ablation is restricted to a subset of glutamatergic neurons that evolve from Lbx1-positive cells, mice develop a phenotype that strongly resembles that of Prrxl1 null mutants, with spinal cord abnormalities and weak responses to pain-related stimuli [15]. The disruption of the Brn3a gene results in impaired projection of DRG and trigeminal ganglion axons to their central target neurons and subsequent apoptosis [16,17], abnormalities that are also observed in Prrxl1 null mutant mice [7,8].…”