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  • Review Article
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Compartments and their boundaries in vertebrate brain development

Nature Reviews Neuroscience volume 6, pages 553–564 (2005)Cite this article

Key Points

  • The embryonic vertebrate hindbrain is subdivided into a series of cell lineage-restricted (that is, cell-tight) compartments known as rhombomeres. The nested expression of Hox genes and the reiterative organization of neurogenesis, proliferation and axonal projections in rhombomeres indicates that the hindbrain is a segmented, metameric structure, similar to the insect body plan. Rhombomere identity is regulated, at least in part, by specific Hox genes or combinations of Hox genes.

  • Various models for a segmental organization of the vertebrate forebrain have been proposed. A prominent recent model suggested a subdivision of the forebrain into six prosomeres. However, only four lineage restriction boundaries have been detected in this area: the transverse boundary between the diencephalon and the midbrain (the DMB), two transverse boundaries that encompass a wedge-shaped area in the presumptive diencephalon that gives rise to the zona limitans intrathalamica (ZLI), and a longitudinal boundary in the telencephalon between the pallium and the subpallium (the PSB).

  • The midbrain–hindbrain boundary (MHB) is a model for a local signalling centre in the emerging vertebrate brain. It regulates the development of its flanking territories through the secretion of fibroblast growth factors (FGFs). Recently, signalling functions have also been revealed for the anterior border of the neural plate (which secretes anti-WNTs and FGFs), for the ZLI (sonic hedgehog), for rhombomere boundaries (WNTs) and for rhombomere 4 (FGFs).

  • The differential response of flanking regions to signals that diffuse from local signalling centres is mediated by a prepattern of transcription factors that are expressed differentially around signalling centres, notably OTX2 (orthodenticle homologue 2) and GBX2 (gastrulation brain homeobox 2) on either side of the MHB, and members of the Iroquois family at the MHB and the ZLI.

  • The localization of boundaries is regulated by global signalling gradients that govern the patterning of the gastrula stage embryo. Both the MHB and the ZLI might be positioned directly by the WNT gradient that polarizes the anteroposterior axis of the early neural plate, and rhombomere boundaries are positioned by graded retinoic acid signalling.

  • It is likely that the establishment of differences in cellular adhesiveness between neighbouring compartments constitutes the first step in forming a boundary between them. Subsequently, specialized boundary features are established. The Notch and WNT pathways have been implicated in this second step, whereas ephrin receptor (Eph)–ephrin signalling seems to be involved in both differential adhesion and cellular repulsion at boundaries.

Abstract

Fifteen years ago, cell lineage restriction boundaries were discovered in the embryonic vertebrate hindbrain, subdividing it into a series of cell-tight compartments (known as rhombomeres). Compartition, together with segmentally reiterative neuronal architecture and the nested expression of Hox genes, indicates that the hindbrain has a truly metameric organization. This finding initiated a search for compartments in other regions of the developing brain. The results of recent studies have clarified where compartment boundaries exist, have shed light on molecular mechanisms that underlie their formation and have revealed an important function of these boundaries: the positioning and stabilization of local signalling centres.

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Figure 1: Boundaries and local signalling centres in the developing vertebrate neural tube.
Figure 2: Hindbrain segmentation.
Figure 3: Formation of and signalling from the zona limitans intrathalamica.
Figure 4: Lineage restriction at and signalling from the chick zona limitans intrathalamica.
Figure 5: Compartment boundaries and local signalling centres in the developing fly wing.
Figure 6: Model for boundary formation.

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Acknowledgements

We thank D. Wilkinson for helpful comments on the manuscript, and both the Medical Research Council and the Wellcome Trust for supporting our work. We apologize to all researchers whose work we could not cite owing to space limitations.

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Authors and Affiliations

  1. Medical Research Council Centre for Developmental Neurobiology, King's College London, Guy's Hospital Campus, London, SE1 1UL, UK

    Clemens Kiecker & Andrew Lumsden

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  1. Clemens Kiecker
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  2. Andrew Lumsden
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Correspondence to Andrew Lumsden.

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DATABASES

Entrez Gene

Dlx

Emx

EphA4

fgf8

Gbx2

Hoxa2

Hoxb1

hoxb1a

Irx2

Krox20

Lfng

Nodal

Otx2

Pax6

pou2

rfng

SFRP2

SHH

Six3

Wnt1

Wnt8b

FURTHER INFORMATION

MRC Centre for Developmental Neurobiology

Glossary

COMPARTMENT

A module of the embryo that consists of polyclonally-related cells that do not mix with cells from neighbouring compartments.

PATTERNING

A developmental process during which cells that are initially equal acquire different identities.

BAUPLAN

German for 'construction plan'.

Hox GENES

A family of developmental regulator genes present in all animal phyla that are arranged in clusters in the genome and encode transcription factors with a DNA-binding homeobox.

SEGMENTATION

The process of dividing an embryonic region into semi-independent, cell lineage-restricted compartments — a way of organizing embryogenesis of a large region by subdividing it into a repetitive series of small fields.

HOMEOTIC SELECTOR GENES

Genes, such as those of the Hox family, that determine the positional identity of the embryonic region in which they are expressed. Absence or ectopic misexpression of such genes results in the lack or duplication of this region (homeotic transformation).

BRANCHIAL ARCHES

(Also called pharyngeal arches). A series of outpocketings in the neck region of an embryo, each of which consists of an epithelial pocket of endoderm and ectoderm that becomes filled by both mesoderm and cranial neural crest-derived mesenchymal cells. The first branchial arch gives rise to the jaws and other head structures.

METAMERIC

A form of segmentation by which all segments show an underlying serial homology.

FLOOR PLATE

The ventral-most longitudinal subdivision of the neural tube of the midbrain and the spinal cord, which acts as a local signalling centre.

VENTRICULAR ZONE

(Also called the proliferative zone). The part of the neuroepithelium that faces the ventricular (inner) surface of the neural tube, where cells are proliferating.

MANTLE ZONE

An outer layer of the neuroepithelium containing postmitotic neurons that have migrated radially away from the ventricular zone.

NEUROMERIC ORGANIZATION

The segmental organization of the neuroepithelium.

LUNATIC FRINGE

A glycosyl transferase that activates the Notch receptor and mediates differential sensitivity to various Notch ligands.

ALLOMETRIC GROWTH

Growth rates of a tissue vary along different axes in space, which drives shape changes of organs during embryogenesis.

AMNIOTE

Birds, reptiles and mammals are all amniotes; that is, their embryos are enclosed within an extraembryonic membrane, the amnion, which contains amniotic fluid. This provides a 'private pond' for the developing embryos of these land-dwelling vertebrates.

ORGANIZER

A small group of cells at the gastrula stage of vertebrate embryos that can induce a secondary embryonic axis in a non-autonomous fashion when transplantated into a host embryo.

GASTRULA

Early embryonic stage during which the just-formed germ layers are reorganized by extensive tissue movements.

COMPETENCE

The ability of a tissue to respond to an inducing signal.

MORPHOLINO ANTISENSE OLIGONUCLEOTIDES

Synthetic oligonucleotides that are exceptionally stable and can serve as tools to block translation or RNA splicing.

ELECTROPORATION

A technique for gene delivery into cells, which allows the transfer of expression plasmids or morpholinos to groups of cells in living embryos.

PITUITARY GLAND

An endocrine gland that forms through an interaction between neuroectoderm and oral ectoderm.

MORPHOGEN

A secreted factor that can induce more than two different cell fates over a sheet of cells in a concentration-dependent manner by forming a gradient.

MESODERM

Germ layer that forms in between ectoderm and endoderm. Mesoderm is crucially involved in neural patterning during gastrulation.

IMAGINAL DISCS

Epithelial pouches in insect larvae that give rise to the sensory organs and body appendages of the adult.

RADIAL GLIA

Glial cells that span the radial axis of neuroepithelium and serve as guidance cues for newly born postmitotic neurons on their way into the mantle zone.

NOTCH

A receptor at the heart of a signalling pathway that regulates a multitude of developmental decisions.

SIGNALLING MODULE

A group of signalling molecules of more than just one pathway that is reiteratively used in different tissues.

SOMITOGENESIS

Segmentation of paraxial mesoderm, which results in the formation of two stripes of distinctive mesodermal blocks along the anteroposterior axis that will give rise to muscle, vertebrae and dermis.

LONG- AND SHORT-GERM DEVELOPMENT

Different modes of insect development; in long-germ insects, all segments are formed from the blastoderm, whereas in short-germ insects, segments are formed by sequential growth.

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Kiecker, C., Lumsden, A. Compartments and their boundaries in vertebrate brain development. Nat Rev Neurosci 6, 553–564 (2005). https://doi.org/10.1038/nrn1702

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