Review
Molecular interactions underlying the specification of sensory neurons

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Sensory neurons of the dorsal root ganglion (DRG) respond to many different kinds of stimulus. The ability to discriminate between the diverse types of sensation is reflected by the existence of functionally and morphologically specialized sensory neurons. This neuronal diversity is created in a step-wise process extending well into postnatal life. Here, we review the hierarchical organization and the molecular process involving interactions between environmental growth factors, used and reused in different developmental contexts in self-reinforcing and cross-inhibitory mechanisms, and intrinsic gene programs that underlie the progressive diversification of sensory progenitors into specialized neurons. The recent advance in knowledge of sensory neuron specification may provide mechanistic principles that could extend to other parts of the nervous system.

Introduction

Understanding cell-type diversification in the neuronal lineage is a challenge owing to the existence of a large number of specialized types with unique molecular and functional properties, morphologies and axonal projections. A central axiom in the determination of neuronal cell fate is the interplay between environmental cues and cell-intrinsic information. As instructive factors and progenitor competence change over time, the cellular response to such external cues will vary between progenitor cells. As a result, the birth of a neuron at a specific time and position in the embryonic body determines its identity.

Development of DRG sensory neurons has emerged as an important example for understanding the finer aspects of neuronal diversification. Following the birth of sensory neurons, immature neurons progress through a series of additional specification steps controlled by dedicated gene programs that, together with environmental cues, orchestrate in a hierarchical process the neuronal subtype-specific identities and axonal projections. DRG neurons derive from neural crest cells that, upon specific inductive signals, delaminate from the dorsal neural tube and migrate along a ventral pathway in chain-like structures and coalesce into ganglia at regular intervals in the anterior half of each somite, adjacent to the neural tube 1, 2. During migration and as neural crest cells start to coalesce into definite ganglia, the pro-neural basic helix–loop–helix (bHLH) transcription factors neurogenin-2 (Ngn2) and neurogenin-1 (Ngn1) are expressed, generating large-size neurons followed by small-size neurons, respectively 1, 3. Approximately 5% of DRG neurons belonging almost exclusively to small-size neurons arise in a later wave of neurogenesis from cells of the boundary cap [4]. Coincident with neurogenesis and cell cycle exit in the coalescing DRG, a few principal sensory sublineages partly with mixed phenotypes appear. These immature neurons eventually undergo a progressive diversification into the many types of sensory neuron of the DRG, including myelinated proprioceptive neurons innervating deep structures, such as Golgi tendon organs (GTO) and muscle spindles, as well as neurons that terminate mainly at cutaneous sites and that differentiate into larger size myelinated low-threshold mechanosensitive neurons transducing sensation of touch, pressure and vibration. Another class of neurons, of smaller size, is unmyelinated or lightly myelinated and involved in nociception (i.e. pain perception), thermoception, pruriception (i.e. itch perception) and gentle touch (C-fiber low-threshold mechanoreceptors). Each type exhibits stereotypical termination patterns within the spinal cord as well as peripherally, in specialized end-organ structures or as free nerve endings (Figure 1).

DRG sensory neuron types can be delineated by the expression of neurotrophic factor receptors, tropomyosin-receptor-kinase A (TrkA), TrkB, TrkC, Met and Ret receptor tyrosine kinases, which serve as receptors for the neurotrophins [nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3)], hepatocyte growth factor (HGF) and glial-derived neurotrophic factor (GDNF) family ligands (GFLs), respectively 1, 5, 6, 7. These receptors are crucial for peripheral innervation of the appropriate targets, cell survival and expression of several ion channels, receptors and other molecular properties defining the functional characteristics of the different types of sensory neuron. Large-diameter DRG neurons conveying low-threshold mechanoreception from the skin express Ret and/or TrkB (in combination, or not, with TrkC); large proprioceptive neurons that sense limb movement and position express TrkC; and small- and medium-diameter neurons, many of which respond to noxious stimuli and mediate pain sensation, express TrkA, Met and/or Ret. Here, we review the remarkable recent advance in understanding of the process of diversification in the sensory lineage involving mechanisms of self-reinforcement and cross-repressive activities by growth factor signaling and transcriptional activities.

Section snippets

Early stages of sensory neuron diversification

Expression of the homeobox transcription factors Islet1 and brain-specific homeobox/POU domain protein 3A (Brn3a) occurs in most or all sensory neurons coincident with cell cycle exit and neurogenesis [8] and suppresses gene programs belonging to the dorsal spinal cord and other cell fates 9, 10. Gene programs activated by these transcription factors partly overlap and analysis of double-knockout mice reveals that, together, they are necessary for most aspects of sensory-specific gene

Early Ret lineage

The recently characterized early Ret (eRet) population (Figure 2, shaded brown) diversifies at later stages into neurons with features of mechanosensory functions [i.e. large-diameter neurofilament (NF) 200+] and may participate in the specific neural circuits that participate in touch sensation [i.e. rapidly adapting low-threshold mechanoreceptors (RA-LTMR) innervating Meissner and Pacinian corpuscles and forming hair follicle lanceolate endings] 6, 7, 23 (Figure 3). These eRet neurons

Transcriptional control of diversification during hierarchical segregation of unmyelinated sensory neurons

The role of Runx1 and growth factor signaling in the regulation of genes defining functional properties of distinct sensory types has been reviewed in recent publications 22, 32, 33 and we refer readers to these for a detailed discussion on this topic. In Figure 2, a proposed organization of the lineage of unmyelinated neurons is presented (shaded red for lTrkA, orange for lRet, blue for TrpM8 and yellow for TH+ neurons). Most, or all, of the unmyelinated neurons are generated from the

Growth factors and sensory neuron diversification

The expression of distinct growth factor receptors in different types of neuron and at different times during development gates for responsiveness to growth factor signaling during embryogenesis and postnatal life (Figure 2). As a general principle, sensory neuron specification involves repetitive use of growth factor signaling (Figure 5) in self-reinforcement and cross-repression activities (Figure 4) that are cell type specific. Mechanisms probably involve both direct and indirect effects on

Concluding remarks

A central question in developmental neurobiology is how progenitor cells are driven to adopt a specific fate among the many possible fates during nervous system development. The principle of cell fate commitment involves organizing centers with patterning morphogens initiating cascades of combinations of transcription factors that together control cell programs. The significant progress made towards understanding the molecular mechanism underlying the diversification of sensory types has

Acknowledgments

This work was supported by the Swedish Research Council, Linnaeus grant (Center for Developmental Biology for Regenerative Medicine), the Swedish Cancer Foundation and Swedish Child Cancer Foundation, the Swedish Brain Foundation, Bertil Hållsten Research Foundation, European UnionFP7 MOLPARK collaborative project, Karolinska Institutet (K.I.) Strategic Neuroscience and Stem cell and Regeneration Program, Wallenberg Scholar and European Research Council (ERC) advanced grant (232675) and K.I.

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