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  • Review Article
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Patterning cell types in the dorsal spinal cord: what the mouse mutants say

Nature Reviews Neuroscience volume 4, pages 289–297 (2003)Cite this article

Key Points

  • Neural activity in the spinal cord enables an animal to sense and respond to stimuli from internal organs and external sensory structures. Broadly speaking, neurons in the ventral half of the spinal cord regulate motor output, whereas neurons in the dorsal half mediate and integrate sensory input. The organization of the mature spinal cord derives from a dorsoventral pattern of cell types that is specified early in neural tube development.

  • Five parallel layers (laminae) have been defined in the dorsal horn of the mature spinal cord, and specific laminae receive input from different sensory modalities through the dorsal root ganglia. Generating the proper connections between the sensory neurons and the neurons of the spinal cord depends on the prior specification of the distinct laminae as target fields for the incoming axons.

  • Four non-overlapping proneural gene expression domains define progenitor cell types in the dorsal neural tube, which generate six types of dorsal interneuron (dI1–dI6). Interneurons derived from Mash1-expressing progenitors contribute to both deep and superficial laminae, whereas Math1-expressing cells migrate exclusively to the deep laminae. Homeodomain transcription factors define region-specific neural identity in the neural tube.

  • The surface ectoderm and notochord specify two secondary signalling centres at the ventral and dorsal midlines of the early neural tube — the floor plate and the roof plate — that produce signals that pattern the neural tube. Sonic hedgehog (Shh) signals from the notochord induce formation of the floor plate, and subsequent Shh expression in the floor plate generates a Shh gradient that promotes the specification of a series of ventral cell types.

  • The roof plate could provide the signals to specify the dorsal cell types of the neural tube — for example, in mice where the roof plate is ablated, dI1–dI3 are not specified. The classic mouse mutant dreher also lacks a roof plate, and the number of early-born dI1 cells is diminished in these mice.

  • Experiments in the chick indicate that bone morphogenetic protein (BMP) 6 and Bmp7 from the roof plate are probably important for specifying dorsal neural fates. Testing the roles of the BMPs in dorsal spinal-cord patterning in the mouse will require the generation of conditional mutants, in which the Bmp genes are inactivated only in the roof plate. Wnt signalling has also been implicated in the patterning of the dorsal neural tube, as have Shh antagonists, such as Gli3 and the Zic family of transcription factors.

  • Ablation experiments indicate that dI1–dI3 are specified by signals from the roof plate, but it is not known what signals direct the development of the dI4–dI6 cells, which arise from more ventral regions. However, experiments in mouse and chick indicate that expression of the Lbx1 homeobox gene normally prevents dI4–dI6 cells from acquiring a dI2–dI4 fate.

  • The mouse mutants do not support a simple morphogen model — such as the Shh model that has been proposed for the ventral neural tube — for dorsal neural tube patterning. However, recent genetic analysis has indicated that factors other than Shh participate in ventral patterning, so similar strategies, albeit different from those that were initially proposed, might be used for ventral and dorsal patterning.

Abstract

The organized arrangement of neurons in the mature spinal cord arises from a pattern of cell types that is established in the embryonic neural tube. Initial research on the molecular mechanisms that underlie this cellular diversity focused on the specification of ventral cell types, but recently more has been learned about cell-type specification in the dorsal neural tube. Genetic loss-of-function analysis in the mouse has provided important insights into the functions of several genes that direct neural cell fate, and we are beginning to define how the organization and connectivity of these neurons is established.

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Figure 1: Organization of the spinal cord.
Figure 2: Migratory paths of neurons from the dorsal neural tube.
Figure 3: A combinatorial code of transcription factors directs the cell type specification in the neural tube.
Figure 4: Dorsal cell specification is disrupted in Gdf7-DTA, dreher and Gdf7 mutant mice.
Figure 5: Dorsal cell specification is altered in Wnt1;Wnt3a double mutant mice.

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Acknowledgements

We are grateful to C. Chesnut, J. Eggenschewiler and J. Timmer for insightful discussions. J. Timmer also contributed through helpful comments on the manuscript. T.C. is a recipient of a Burroughs Wellcome Fund Hitchings-Elion Fellowship. In this lab, research on the genetics of neural tube development in the mouse is funded by NIH Grants.

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Authors and Affiliations

  1. Developmental Biology Program, Sloan-Kettering Institute, 1275 York Avenue, New York, 10021, New York, USA

    Tamara Caspary & Kathryn V. Anderson

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  1. Tamara Caspary
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  2. Kathryn V. Anderson
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Correspondence to Kathryn V. Anderson.

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DATABASES

LocusLink

Bmpr

Brn3a

dreher

Emx2

Gdf7

Gli3

Irx3

Lbx1

Lh2a

Lh2b

Lim1

Lim2

Lmx1a

Lmx1b

Mash1

Math1

Msx

nestin

Ngn1

Ngn2

Pax2

Pax3

Pax7

Rab23

Rnx/Tlx3

Shh

Wnt1

Wnt3a

Zic

FURTHER INFORMATION

Encyclopedia of Life Sciences

neural crest: origin, migration and differentiation

neuronal subtype identity regulation

vertebrate embryo: patterning of the neural crest lineage

Glossary

HEDGEHOG FAMILY

A group of signalling molecules with several roles during development. It includes Hedgehog, which specifies the segmental polarity of the blastoderm and cell fate in imaginal discs of Drosophila: Sonic hedgehog, which participates in many aspects of neural development in vertebrates; Indian hedgehog, which participates in endoderm differentiation and bone growth; and Desert hedgehog, which is involved in spermatogenesis.

DORSAL ROOT GANGLIA

Paired ganglia that lie alongside the spinal cord and contain the cell bodies of sensory neurons.

MANTLE LAYER

A layer of cells in the developing spinal cord that gives rise to the grey matter. It is initially generated by the migration of neuroblasts from the ventricular zone.

BASIC HELIX–LOOP–HELIX

A structural motif that is characterized by two α-helices separated by a loop. The helices mediate dimerization, and the adjacent basic region is required for DNA binding.

HOMEODOMAIN

A 60-amino-acid DNA-binding domain that comprises three α-helices.

COMMISSURAL

A term that refers to neuronal projections that span the midline of the brain or spinal cord.

DII

A lipophilic dye that emits an intense fluorescence when incorporated into cell membranes. It is commonly used to track cell migration, or for the retrograde or anterograde tracing of axons.

PROPRIOCEPTIVE

Relating to the perception of position and movement of the body parts in response to stimuli generated within the body.

GREEN FLUORESCENT PROTEIN

(GFP). Fluorescent protein cloned from the jellyfish Aequoria victoria. The most frequently used mutant, enhanced GFP, is excited at 488 nm and has an emission maximum at 510 nm.

NOCICEPTIVE

Referring to the perception of painful stimuli.

NOTOCHORD

A rod-like structure of mesodermal origin that is found in vertebrate embryos. Signals from the notochord participate in the differentiation of the ventral neural tube and in the specification of motor neurons.

BONE MORPHOGENETIC PROTEINS

(BMPs). Multifunctional secreted proteins of the transforming growth factor-β superfamily.

NEURAL CREST

Groups of cells that migrate from the neural tube to the periphery, where they give rise to a wide variety of cell types.

CHOROID PLEXUS

A site of production of cerebrospinal fluid in the adult brain. It is formed by the invagination of ependymal cells into the ventricles, which become richly vascularized.

CRE RECOMBINASE

Part of a site-specific recombination system derived from Escherichia coli bacteriophage P1. Two short DNA sequences (loxP sites) are engineered to flank the target DNA. Activation of the Cre recombinase enzyme catalyses recombination between the loxP sites. If the loxP sequences are arranged as a direct repeat, recombination will delete the DNA between the sites, leading to excision of the intervening sequence.

ZINC FINGER

A protein module in which cysteine or cysteine–histidine residues coordinate a zinc ion. Zinc fingers are often used in DNA recognition and in protein–protein interactions.

HYPOMORPHIC

A mutation that does not eliminate the wild-type function of a gene and gives a less severe phenotype than a loss-of-function mutation.

PARAXIAL MESODERM

A region of the mesoderm adjacent to the notochord, which becomes segmented rostrocaudally to give rise to the somites early in development.

VENTRICULAR ZONE

The proliferative inner layer of the neural tube.

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Caspary, T., Anderson, K. Patterning cell types in the dorsal spinal cord: what the mouse mutants say. Nat Rev Neurosci 4, 289–297 (2003). https://doi.org/10.1038/nrn1073

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