The ability to perceive and respond to diverse noxious environmental stimuli, such as temperature (heat, cold), mechanical force (pinprick, pinch), and chemicals, is essential for keeping animals and humans away from damage. These stimuli are detected and encoded by nociceptors, a specialized group of somatosensory neurons with primary afferent fibers innervating the skin and with cell bodies located in the trigeminal and dorsal root ganglia (DRG) [1]. Mounting evidence indicates that various nociceptors have distinct morphological, physiological, and molecular properties. In the past decades, basic understanding of how diverse nociceptive information is sensed and transmitted has been greatly expanded with the extensive identification and functional interpretation of primary sensory neuronal categories. In contrast to noxious heat and cold information, which is almost exclusively detected and conveyed by transient receptor potential channels (TRPV1 and TRPM8) and unmyelinated C-fibers [2], mechano-nociceptors exhibit more complicated characteristics and include at least a subset of unmyelinated C-fibers (Mas-related G-protein-coupled receptor type D-positive) which transmit light punctuate pressure, and myelinated A-fibers [neurons of the neuropeptide Y receptor 2 (Npy2r+) lineage], which transmit sharp pinprick information [3]. While Npy2r has been associated with A-fiber mechano-nociceptors, the precise distribution of Npy2r in DRG neurons is still obscure, given the contradictory results from different studies [4,5,6]. In addition, the differentiation and segregation of mechano-nociceptors during development are still not fully understood. The transcription factors involved in the genetic control of mechano-nociceptors from different linages also need to be identified.

In the current issue of Neuroscience Bulletin, Qi and colleagues first clarified the expression of Npy2r in developing DRG neurons at different stages [7]. Based on the results of combining Npy2r in situ hybridization with NF200 immunostaining, they demonstrated that Npy2r+ neurons show two expression patterns: (1) myelinated NF200+ neurons express Npy2r transiently, as the expression level gradually decreases from 40% on postnatal day 0 (P0) to zero on P30, and (2) unmyelinated NF200– neurons persistently expressing Npy2r along with co-expression of the pruriceptor marker Nppb (natriuretic peptide type B). Their findings provide evidence to support the stage-dependent expression of Npy2r during development in mouse DRG neurons. Although Npy2r+-lineage neurons have been shown to respond to sharp, noxious mechanical stimuli, it is necessary to discriminate the possible functional discrepancy between neurons that transiently or persistently express Npy2r. Meanwhile, even though a previous study has proposed that activity of the proneural factors Neurogenin2 (Ngn2) and Ngn1 directs neural crest cells to the DRG sensory lineage during development [8], the specific neurogenetic control of mechano-nociceptors remains unclear.

Subsequently, the authors explored whether the development of these two subpopulations of Npy2r+-lineage DRG neurons were regulated by the same or different transcription factors. Interestingly, they found that nuclear factor I/A (NFIA) was required for the development of neurons that expressed Npy2r both transiently and persistently, as the conditional knockout (CKO) of NFIA in DRG neurons led to the complete elimination of Npy2r expression after birth (P0, P7, and P30). Consistent with previous reports, the other transcription factor, runt-related transcription factor 1 (Runx1), was only necessary for the development of neurons that persistently express Npy2r and Nppb+ [9], but was dispensable for the myelinated neurons transiently expressing Npy2r, since the percentage of Npy2r and NF200 was unaffected at P7 in Runx1-CKO mice compared with wild-type mice.

More importantly, the pinprick-evoked response of NFIA CKO mice was impaired, while other somatic sensations like light touch, heat and cold were intact. Nonetheless, acute sharp mechanical stimuli still induced c-Fos in the dorsal horn of Runx1-CKO mice, suggesting unaffected responses to pinprick in these mice. As noted above, NFIA controlled the development of the entire Npy2r lineage, and Runx1 controlled the development of neurons that persistently expressed Npy2r. The behavioral results from transgenic mice indicated that subcategories of Npy2r lineage neurons played distinct roles in the transmission of mechanical nociceptive and pruritic information. In contrast to the unmyelinated Npy2r+ NF200- group, the myelinated NF200+ group transiently expressing Npy2r before maturation exclusively participated in the perception and conduction of mechanical nociceptive information (Fig. 1).

Fig. 1
figure 1

The NF200+ DRG neurons that transiently express Npy2r respond to pinprick stimulation and are controlled by transcription factor NFIA during development.

Full size image

The molecular mechanism underlying cell fate specification in the neuronal lineage is an important issue in developmental neurobiology. Several transcription factors have been identified that regulate the development of peripheral nociceptors. Here, Qi and colleagues establish that NFIA plays an essential role in the emergence of A-fiber mechano-nociceptors in sensory ganglia. This finding improves the understanding of the neurogenetic control of somatosensory neuronal development. Mechanistically, the distinct regulation during development in neurons transiently and persistently expressing Npy2r by NFIA and Runx1 will allow further dissection of the molecular and functional properties of these two genetically-defined subpopulations. Given that other mechanotransducers such as Piezo2 also contribute to the sensitivity of myelinated mechano-nociceptors, whether Piezo2 channels are expressed on Npy2r lineage mechano-nociceptors and regulated by NFIA deserve further investigation. Since recent studies suggest that Npy2r signaling controls the transmission of mechanical pain under physiological conditions [10], the roles of Npy2r and NFIA in chronic pain need to be addressed as well. Finally, the findings also raise the question as to which molecules downstream of Npy2r associated with A-fiber mechano-nociceptors are engaged in sensing and processing mechanical pain, which will provide a more comprehensive map of the mechanical pain pathway.