Specification of dorsal spinal cord interneurons

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Abstract

To obtain the correct number of each neuronal subtype, there must be mechanisms to control progenitor pool size, and factors that control the differentiation of these progenitors into specific types of neurons. In the dorsal spinal cord, recent advances have begun to define these mechanisms. Eight dorsal interneuron populations have now been classified according to their expression of molecular markers, their projection patterns, neurotransmitter type, and/or function. The ability to identify progenitor cells and neurons in the dorsal spinal cord on the basis of the genes they express has provided a framework for identifying extrinsic factors that establish proliferation rate and dorsal–ventral polarity in the developing neural tube; furthermore, this ability has helped define roles for basic helix–loop–helix and homeodomain transcription factors in neuronal cell-type specification.

Introduction

How one perceives sensory input from both the external and internal environments requires multiple levels of organization in the nervous system. The dorsal spinal cord plays a critical role in organizing responses to sensory input, as it contains the neurons that integrate and relay somatosensory information entering the spinal cord from sensory neurons in the periphery to central targets. The identification of the different types of dorsal spinal cord neurons and an appreciation of how they develop from the embryonic neural tube are essential for understanding somatosensory perception.

As the neural tube forms, three classes of cells arise in the dorsal region. The roof plate forms at the dorsal midline and serves as an important signaling center for patterning the neural tube. Neural crest cells delaminate and migrate into the periphery, and the remaining cells comprise the dorsal neural progenitor cells that will give rise to the dorsal sensory interneurons. This stereotypical organization of the spinal cord results from the integration of extrinsic and intrinsic signals that control the proliferation and diversification of distinct neuronal subtypes. This organizational strategy is achieved initially by the response of neuronal precursors to a field of opposing inductive signals from the dorsal and ventral midlines. Sonic hedgehog (Shh) and bone morphogenetic proteins (BMPs) have emerged as the pre-eminent inductive signals involved in dorsoventral (DV) patterning of the neural tube (reviewed in 1., 2.). The read-out of these inductive signals involves alterations in gene expression of regulatory transcription factors, such as homeodomain (HD) and basic helix–loop–helix (bHLH) factors, which serve to control the complex interplay between cell cycle maintenance and neuronal differentiation. Although it is clear that the roof plate and BMPs have an important role in DV polarity in the neural tube, many questions remain to be answered about the precise role of inductive signals in the timing of proliferation, differentiation, and specification of dorsal interneuron cell types. In this review, we examine recent advances in defining dorsal interneuron populations, and in defining both the signalling pathways and the transcription factors that are important in specifying these neurons.

Section snippets

Defining dorsal interneuron populations

Defining progenitors and populations of neurons by combinatorial expression of transcription factors in the ventral neural tube has been instrumental in our understanding of the logic underlying the development of the spinal cord 3., 4.. Recently, similar efforts in defining dorsal interneuron populations have culminated in the establishment of a model of dorsal spinal development comprised of eight distinct interneuron subtypes, defined mainly by expression of homeodomain factors, but also by

Transcriptional control of cell-type specification

The signaling molecules involved in setting up the DV axis in the neural tube do so by incurring changes in the expression of transcription factors. Much has been learned of these processes in the ventral neural tube, where Shh signaling modulates the expression of HD transcription factors (reviewed in [3]). Recently, transcription factors involved in neuronal cell-type specification in the dorsal neural tube have also been identified. As in the ventral neural tube, many of these transcription

Conclusions and future directions

Increasing evidence places BMP signaling as an early event in the specification of dorsal identity in the spinal neural tube. These signals appear to initiate multiple pathways, some of which appear antagonistic, that serve to modulate cell number as well as cell-type specification (Figure 2). Currently, there is a drive towards ascribing a discrete function to each molecule in these pathways (i.e. a proliferation factor, differentiation factor, specification factor, or pro-apoptotic factor).

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • of special interest

  • ••

    of outstanding interest

Acknowledgements

We thank John Timmer, Ying Liu, David Panchision and Qiufu Ma for their helpful comments on this manuscript.

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