Getting in touch with your senses: Mechanisms specifying sensory interneurons in the dorsal spinal cord

Abstract

The spinal cord is functionally and anatomically divided into ventrally derived motor circuits and dorsally derived somatosensory circuits. Sensory stimuli originating either at the periphery of the body, or internally, are relayed to the dorsal spinal cord where they are processed by distinct classes of sensory dorsal interneurons (dIs). dIs convey sensory information, such as pain, heat or itch, either to the brain, and/or to the motor circuits to initiate the appropriate response. They also regulate the intensity of sensory information and are the major target for the opioid analgesics. While the developmental mechanisms directing ventral and dorsal cell fates have been hypothesized to be similar, more recent research has suggested that dI fates are specified by novel mechanisms. In this review, we will discuss the molecular events that specify dorsal neuronal patterning in the spinal cord, thereby generating diverse dI identities. We will then discuss how this molecular understanding has led to the development of robust stem cell methods to derive multiple spinal cell types, including the dIs, and the implication of these studies for treating spinal cord injuries and neurodegenerative diseases. This article is categorized under: Neurological Diseases > Stem Cells and Development.

Keywords: bone morphogenetic proteins; cell fate specification; dorsal sensory interneurons; regeneration; spinal cord.

FIGURE 1

Patterning and functional organization of dorsal sensory interneurons (dIs). (a) The spinal cord is patterned along the dorsal–ventral axis using signals that include: the roof plate (RP)‐derived Bmps and Wnts, presomitic mesoderm (PM)‐derived RA and floor plate (FP)‐derived Shh. (b) In the dorsal spinal cord, the combinatorial activities of RP‐ and PM‐derived signals result in the specification of six progenitor domains (dP1–dP6) which differentiate to generate six classes of dI neurons (dI1–dI6s). (c,d) Both dorsal progenitors (dPs, c) and differentiated neurons (dIs, d) can be identified by their expression of specific transcription factors. (e,f) Hamilton Hamburger (HH) 24 chicken spinal cord section immunostained for the complements of transcription factors that permit the identification of six classes of dIs (dI1–dI6s). (g) Schematic depicting the organization and function of somatosensory circuits in the adult spinal cord. The dIs migrate from their embryonic positions to occupy different laminae in the adult dorsal horn (Rexed, 1954). Peripheral afferents carrying different sensory stimuli synapse onto specific layers, where the dorsal interneurons process this information before sending it to the brain or ventral spinal cord

FIGURE 2

Models for Bmp‐mediated patterning of the dorsal spinal cord. (a) In the morphogen model, RP‐derived Bmps act in a concentration dependent manner to specify the RP itself, and the dI1, dI2 and dI3 populations of interneurons. (b) If Bmps function as a collective morphogen, then the highest concentration of Bmps would specify the RP and dI1 fates while successively lower concentrations of Bmps would progressively specify the dI2 and dI3 fates. (c) However, experimental observations using chicken embryos and mESCs as model systems, rather support an alternative “signal‐specific model” of Bmp function. In this model, each Bmp specifies a range of cellular fates. For example, Bmp4 was shown to direct cells mostly towards the dI1 or dI2 fates, with some RP or dI3 fates, while Bmp7 directs cells towards the RP fate, with some dI1or dI3 fates. A high level of the Bmp is most effective at directing a specific range of cell types, whereas a lower level of the Bmp is less effective at directing the same range of cell types. (d–g) Schematics of a “mix and match” Bmp code that acts reiteratively to specify RP, dI1s, dI2s, and dI3s. In this model, Bmp7 (mouse) and Bmp7 (chicken) act though Bmpr1a to specify the RP identity (d). Both Bmp4 and Bmp7 act through Bmpr1a to direct dP1s to proliferate but only Bmp4 can promote dP1s to differentiate acting through Bmpr1b (e). However, only Bmp4 can block dP2 proliferation and promote them to differentiate into dI2s, through Bmpr1b (f). All tested Bmps can direct dP3s to proliferate and differentiate into dI3s (g)

FIGURE 3

Oscillation model for dI differentiation. (a) Schematic of embryonic spinal cord depicting the ventricular zone (VZ) and marginal zone (MZ) where neural progenitors and mature neurons reside. (b) In the VZ, oscillatory expression of bHLH transcription factors such as Atohl1, Ascl1, and Neurog1/2, and Hes1 maintains progenitors in a proliferative state. Sustained, elevated expression of the bHLH genes and decreased expression of Hes genes prompt progenitors to exit the cell cycle, migrate into the transition zone (TZ) and commit to neurogenesis. The levels of bHLH gene expression then rapidly diminishes as neurons finish their migration into the MZ. The transition of committed neural progenitors to mature neurons is marked by the upregulation of the pan‐neuronal marker tubulin‐III (Tubb3). (c) In dividing neural progenitors, the oscillatory expression of bHLH and Hes genes occurs by activating notch‐delta signaling. High bHLH expression in progenitor 1 leads to delta accumulation on the cell surface which activates notch signaling in its neighbor, progenitor 2, and thereby elevates Hes1 expression. Through a negative feedback loop, high levels of Hes1 in progenitor 2 now suppresses Hes1, allowing bHLH gene expression to recommence, such that the cycle begins again. The periodic activities of notch‐delta signaling, and the negative feedback loop that regulates Hes1, keeps the expression of Hes1 in oscillation with the bHLH genes and maintains the neural progenitors in a proliferative state