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  • Review Article
  • Published:

Specification and connectivity of neuronal subtypes in the sensory lineage

Nature Reviews Neuroscience volume 8, pages 114–127 (2007)Cite this article

Key Points

  • The nervous system consists of a vast number of different types of neuron. How different types of neuron form and how axons can project over long distances and make highly specific contacts to establish a functional circuit remain largely unknown.

  • We provide an overview of the spatial and temporal sequence of how neuronal diversification emerges in the sensory neuron lineage and how it is genetically coordinated with other developmental processes during the same period of development.

  • We outline the relationship between the gene programmes driving multipotency, neurogenesis and sensory specification and discuss the relation of transcription factors to sensory subtype diversification.

  • This review illustrates how, during development, one transcription factor can coordinate different developmental processes necessary for building a functional circuit.

  • In many parts of the nervous system, neuronal subtypes are produced before precise and unique connection patterns exist. Recent data on the runt-related transcription factor (RUNX) family of transcription factors give an example of how, in a context-dependent manner, RUNX1 and RUNX3 drive key aspects of the establishment of the nociceptive, mechanoreceptive and proprioceptive subclasses of sensory neuron, from identity to modality-specific contact characteristics.

  • RUNX transcription factors act both as transcriptional repressors and activators at different times in development, driving the expression of genes that molecularly and functionally characterize different subtypes of sensory neuron.

  • We also discuss how these transcription factors might be acting cell-autonomously to affect neuronal propensity for axonal growth and susceptibility to cell death.

Abstract

During the development of the nervous system, many different types of neuron are produced. As well as forming the correct type of neuron, each must also establish precise connections. Recent findings show that, because of shared gene programmes, neuronal identity is intimately linked to and coordinated with axonal behaviour. Peripheral sensory neurons provide an excellent system in which to study these interactions. This review examines how neuronal diversity is created in the PNS and describes proteins that help to direct the diversity of neuronal subtypes, cell survival, axonal growth and the establishment of central patterns of modality-specific connections.

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Figure 1: Neural crest migration, sensory neurogenesis and the establishment of modality-specific connections.
Figure 2: Three waves of neurogenesis in the sensory neuron lineage.
Figure 3: Genetic cascades that control neurogenesis and subtype specification.
Figure 4: Functions of RUNX proteins in the establishment of central projection.
Figure 5: Graded RUNX activity controls sensory neuron axonal outgrowth.

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Acknowledgements

This work was supported by the Swedish Medical Research Council and the Swedish foundation for strategic research (CEDB grant). We thank J. Hjerling-Leffler for help with the design of figure 1.

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  1. Section of Molecular Neurobiology, Karolinska Institutet, MBB, Scheeles vg 1, S17 177, Stockholm, Sweden

    Frédéric Marmigère & Patrik Ernfors

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Glossary

Neurotrophic tyrosine receptor kinases

(Trks). Trk receptors are high-affinity tyrosine kinase receptors for the neurotrophins, with TrkA mainly activated by nerve growth factor, TrkB by brain-derived neurotrophic factor and neurotrophin 4 (NT4), and TrkC by NT3.

Basic helix-loop-helix

Protein structural motif characterized by two α-helices connected by a loop, with one helix containing basic amino acids facilitating DNA binding. This motif is present in certain families of transcription factors.

Proneural gene

Generic name for genes expressed in neural progenitors that promote pan-neuronal differentiation.

POU homeodomain

Family of homeodomain transcription factors containing a shared additional conserved sequence adjacent to the homeodomain referred to as POU (bipartite DNA-binding domain) and named after the initials of the founder members: PIT1, OCT1/2 and UNC86.

Zinc finger

Small structural domain found in several DNA interacting proteins organized around a zinc ion, consisting of two antiparallel β-strands and an α-helix.

Ia muscle spindle afferent

Proprioceptive sensory afferent innervating the muscle spindles in the periphery and α-motor neuron centrally, distinct from the Ib afferent which innervates the Golgi tendon organs in the periphery.

α-motor neuron

Large motor neuron located in the spinal cord and the brainstem innervating extrafusal muscle fibres of skeletal muscle and responsible for their contraction, distinct from γ-motor neurons that innervate intrafusal muscle fibres.

Ret

Tyrosine kinase receptor activated by the glial cell line-derived neurotrophic factor family of ligand and named after rearranged during transformation because it is mutated in several cancer syndromes.

ETS transcription factor

One of the largest families of transcription factors that retains a region of conserved sequence, the ETS (E twenty-six) domain forming the winged helix-turn-helix DNA binding domain is composed of three α-helices and a four-stranded β-sheet.

Dorsal funiculus

Division of the white matter in the spinal cord consisting of a bundle of the nerves projecting from the dorsal root ganglion.

Short interfering RNA

(siRNA). Short double-stranded RNA molecules that silence gene expression in a sequence-specific manner by a process termed RNA interference. The 2006 Nobel Prize in Physiology or Medicine was given to the discovery of RNA interference.

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Marmigère, F., Ernfors, P. Specification and connectivity of neuronal subtypes in the sensory lineage. Nat Rev Neurosci 8, 114–127 (2007). https://doi.org/10.1038/nrn2057

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