A Transcription Factor Code Defines Nine Sensory Interneuron Subtypes in the Mechanosensory Area of the Spinal Cord

Abstract

Interneurons in the dorsal spinal cord process and relay innocuous and nociceptive somatosensory information from cutaneous receptors that sense touch, temperature and pain. These neurons display a well-defined organization with respect to their afferent innervation. Nociceptive afferents innervate lamina I and II, while cutaneous mechanosensory afferents primarily innervate sensory interneurons that are located in lamina III–IV. In this study, we outline a combinatorial transcription factor code that defines nine different inhibitory and excitatory interneuron populations in laminae III–IV of the postnatal cord. This transcription factor code reveals a high degree of molecular diversity in the neurons that make up laminae III–IV, and it lays the foundation for systematically analyzing and manipulating these different neuronal populations to assess their function. In addition, we find that many of the transcription factors that are expressed in the dorsal spinal cord at early postnatal times continue to be expressed in the adult, raising questions about their function in mature neurons and opening the door to their genetic manipulation in adult animals.

Delineating the Diversity of Spinal Interneurons in Locomotor Circuits

“…Shox2 is expressed postmitotically in a subset of the V2a cells and several interneuronal populations in the dorsal spinal cord. Silencing of all Shox2 neurons decreased the locomotor frequency; however, selective ablation of Shox2ϩ V2a interneurons had no effect on the rhythm (Dougherty et al, 2013). This suggests that the non-V2a subset of Shox2 neurons contributes to rhythm generation.…”

“…The V2 population emerge from Lhx3-expressing progenitor cells and can be divided into two subsets, V2a and V2b interneurons, through mechanisms involving Notch/Delta signaling and the transcription factors Foxn4, Tal1, and Lmo4 (Peng et al, 2007;Kimura et al, 2008;Joshi et al, 2009, Del Barrio et al, 2013, Li et al, 2005. Unlike V1 interneurons, which are thought to be exclusively inhibitory, the V2 population consists of the GABAergic/ glycinergic V2b neurons that express Gata2/3, as well as excitatory V2a cells that express Chx10 (Lundfald et al, 2007;Peng et al, 2007).…”

“…Unlike V1 interneurons, which are thought to be exclusively inhibitory, the V2 population consists of the GABAergic/ glycinergic V2b neurons that express Gata2/3, as well as excitatory V2a cells that express Chx10 (Lundfald et al, 2007;Peng et al, 2007). These two subsets are born simultaneously in a mosaic manner during early postmitotic neurogenesis (Joshi et al, 2009, Del Barrio et al, 2013). Although the role of the V2b cells in ipsilateral flexor-extensor alternation has come to light recently (see above), the V2a cells were the first subset of this population to be characterized and shown to be involved in left right alternation (Crone et al, 2008;Crone et al, 2009).…”

“…These domains produce 11 cardinal interneuron classes in the spinal cord (dI1-dI6, V0 -V3) and the motoneurons (Goulding and Pfaff, 2005; Alaynick et al, 2011;Catela et al, 2015). Identification of the specific transcription factor profiles of each neuronal population have allowed groups of molecularly related cells in the spinal cord to be targeted and characterized reliably (Jessell, 2000;Grillner and Jessell, 2009;Arber, 2012).…”

Making sense out of spinal cord somatosensory development

“…TRPM8 (Bautista et al, 2007), TRPV1 (Villeda et al, 2006), MRGPRD (Zylka et al, 2005), SP, CGRP, IB4, TRKA (Snider and McMahon, 1998), VGLUT3 (Seal et al, 2009), TRKB, NPY2R (Li et al, 2011), TRKC, PV (Arber et al, 2000), VGLUT1, Vglut1 (Alvarez et al, 2004;Hantman and Jessell, 2010;Llewellyn-Smith et al, 2007), NK1R, PKCγ (Todd, 2010), Grpr (Sun and Chen, 2007), Som, Dyn (Duan et al, 2014;Xu et al, 2008), LMX1B, RORα, MAFA, LBX1, TLX3, PAX2, GBX1 (Bourane et al, 2015b;Del Barrio et al, 2013;Szabo et al, 2015), Npy (Bourane et al, 2015a). of the direct downstream targets of these TFs that could connect them to terminal differentiation processes such as axon guidance and neurotransmitter or neuropeptide fate (Avraham et al, 2009;Brohl et al, 2008;Cheng et al, 2004Cheng et al, , 2005Hobert, 2011;Pillai et al, 2007).…”