Prrxl1 is required for the generation of a subset of nociceptive glutamatergic superficial spinal dorsal horn neurons

Abstract

Perception of noxious events relies on activation of complex central neuronal circuits. The spinal cord dorsal horn plays a pivotal role in the process relaying to the brain various types of somatosensory input. These functions are accomplished by distinct sensory neurons specifically organized in different laminae. They differentiate during development in a spatial-temporal order due to the expression of combinatorial sets of homeodomain transcription factors. Here we demonstrate that the differential expression of the homeodomain transcription factors Prrxl1 (DRG11), Tlx3, and Lmx1b defines various subpopulations of spinal cord dorsal horn glutamatergic early born and late born neurons. Accordingly, in the superficial dorsal horn of Prrxl1 2/2 mice, the number of glutamatergic neurons is reduced by 70%, while the number of Golgi-impregnated and noxious-induced Fos immunoreactive neurons is reduced by 85%. These results suggest a crucial role for Prrxl1 in the generation of various subpopulations of nociceptive glutamatergic superficial dorsal horn neurons. Developmental Dynamics 239:1684-1694,

Paired related homeobox protein‐like 1 (Prrxl1) controls its own expression by a transcriptional autorepression mechanism

“…This study addresses the transcriptional control mechanisms of Prrxl1, a homeobox gene critical for proper assembly of DRG-dorsal SC pain circuitry [5,20,22]. ChIP performed with chromatin derived from embryonic DRG and dorsal SC identified two regions (in the proximal promoter and intron 4 of Prrxl1 locus) that show tissue specific recruitment of Prrxl1.…”

“…In the DRG, the pan-sensory HD transcription factors Pou4f1 and Isl1 are both required for Prrxl1 expression [11]. On the other hand, in developing dorsal SC, Tlx1/ 3 and Lmx1b are extensively co-expressed with Prrxl1 [22,23]. Prrxl1 appears to depend more on Lmx1b than on Tlx1/3, as in Lmx1b null mice Prrxl1 expression was completely abolished [9], whereas in Tlx1/3 null mutant mice Prrxl1 expression was normally initiated but completely lost by E14.5 [19].…”

“…Small-diameter afferent fibers terminating in the superficial dorsal horn develop normally up to birth, although with retarded penetration in the spinal dorsal horn, and a significant fraction of which undergoes apoptosis at early post natal life [5,20]; at the spinal level, abnormal migration and differentiation followed by marked death of superficial dorsal horn neurons takes place during embryonic development [5,9,22]. In line with these nociceptive circuitry developmental defects, adult Prrxl1 À/À mice displayed a substantial reduction in sensitivity to a broad range of noxious stimuli [5].…”

Several Cis-regulatory Elements Control mRNA Stability, Translation Efficiency, and Expression Pattern of Prrxl1 (Paired Related Homeobox Protein-like 1)

“…It would be interesting to assess if one possible RRB binding candidate could be Tlx3 as this transcription factor induces Prrxl1 promoter activity (Fig. 7A) and highly co-localizes with Prrxl1 (10).…”

“…Nevertheless, the role of Prrxl1 in these tissues is poorly studied. Prrxl1 null mutant mice present a distorted spinal dorsal horn with scarce superficial nociceptive-responsive neurons (8 -10), reduced DRG neuronal population (10), and a marked decrease in nociceptive response capacity in various pain tests (8). Interestingly, although involved in the embryonic differentiation of various subpopulations of superficial dorsal horn excitatory neurons (10), Prrxl1 appears not to be required for the normal development of DRG neurons before birth but rather to be essential for their survival in early postnatal life (9).…”