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Patterning the cranial neural crest: Hinbrain segmentation and hox gene plasticity

Key Points

  • Craniofacial development is closely related to the segmentation of the hindbrain into rhombomeres. This segmentation is critical for the appropriate development of several cranial nerves as well as for defining the migration pathways of the neural crest cells towards the periphery.

  • There is a molecular correlate of hindbrain segmentation, as the expression of two gene families are essential for establishing compartments and imposing segmental identity — the ephrin/Eph receptors and the Hox transcription factors. The expression of the Hox genes is not exclusive to the hindbrain itself, but it is also evident in the neural crest cells that populate the branchial arches, providing further evidence that hindbrain segmentation has direct effects on craniofacial patterning.

  • Early experiments grafting avian neural crest primordia to ectopic locations indicated that the morphogenetic programme and the Hox gene code of the neural crest cells is acquired before migration from the neural tube and is merely carried to the periphery. This idea has been also favoured by rhombomere-transplantation experiments to sites anterior to the otic vesicle.

  • More recent experiments have shown that the morphogenetic programme and Hox gene expression are not irreversibly committed but can show plasticity. Chick rhombomere transplantations to locations caudal to the otic vesicle, as well as rhombomere rotations and ablations, have shown that environmental factors can influence the fate of migratory neural crest cells, although the evidence has not been entirely homogeneous.

  • Observations made in other species have also provided evidence for Hox gene expression plasticity. Grafting of small numbers of cells has revealed that the size of the cell community is an important determinant of the degree of plasticity such that smaller grafts or individual cells are more sensitive to environmental cues. Indeed, this dependence on community size could potentially help to explain the heterogeneity of the observations made in chick embryos.

  • Regulatory sequences that drive the region-specific expression of Hox genes have begun to be identified. Although more cases need to be investigated, it is possible that independent regulatory elements may be used for controlling their expression in mesenchymal versus neurogenic neural crest cell derivatives.

  • The plasticity observed at the single cell level induce by environmental cues may be important for the establishment of precise boundaries in the hindbrain. This phenomenon in combination with the ephrin/Eph receptor-mediated segregation may provide a mechanism for the generation of precise rhombomeric territories during development.

Abstract

Understanding the patterning mechanisms that control head development — particularly the neural crest and its contribution to bones, nerves and connective tissue — is an important problem, as craniofacial anomalies account for one-third of all human congenital defects. Classical models for craniofacial patterning argue that the morphogenic program and Hox gene identity of the neural crest is pre-patterned, carrying positional information acquired in the hindbrain to the peripheral nervous system and the branchial arches. Recently, however, plasticity of Hox gene expression has been observed in the hindbrain and cranial neural crest of chick, mouse and zebrafish embryos. Hence, craniofacial development is not dependent on neural crest pre-patterning, but is regulated by a more complex integration of cell and tissue interactions.

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Figure 1: Hindbrain segmentation and gene expression.
Figure 2: Plasticity of Hox gene expression in the hindbrain and neural crest cells.
Figure 3: Regulation of Hoxa2 and Hoxb1 in hindbrain and neural crest cells.
Figure 4: Mechanism for hindbrain segmentation and the establishment of Hox gene expression domains.

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Acknowledgements

We thank members of the lab for valuable discussions and T. Schilling for communicating results before publication. P.T. was supported by EMBO and HFSP postdoctoral fellowships and R.K. by Core MRC Programme support and an EEC Biotechnology Network grant.

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Glossary

PARAXIAL MESODERM

Region of the mesoderm adjacent to the notochord, which becomes segmented rostro-caudally to give rise to the somites early in development.

NEURAL CREST

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

MESENCHYME

Undifferentiated connective tissue present in the early embryo.

HINDBRAIN

Division of the nervous system that consists of the pons, the cerebellum and the medulla. It is derived from the rhombencephalon, one of the three primary embryonic vesicles of the neural tube.

HOX GENES

Transcription factors expressed in specific patterns, which are important for determining regional identity along the antero-posterior axis in the embryo. They are also known as homeobox genes.

CRANIAL GANGLIA

Groups of neurons that carry somatosensory information from the head and neck to the central nervous system.

BRANCHIOMOTOR NERVES

Cranial nerves that control muscles derived from the branchial arches. In humans, they are the trigeminal, the facial, the glossopharyngeal, the vagus and the spinal accessory nerves.

BRANCHIAL ARCHES

Structures populated by neural crest cells found in the early embryo, which give rise to most facial structures in the adult.

MOSAIC

Tissue containing two or more genetically distinct cell types.

DOMINANT-NEGATIVE

A mutant protein capable of forming a heteromeric complex with the normal molecule, knocking out the activity of the entire complex.

OTIC VESICLE

Ectodermal invagination that constitutes the primordium of the internal ear.

SOMITES

Axial blocks of mesoderm along the vertebrate axis that differentiate into skin, bone and muscle.

MESENCEPHALON

One of the three primary embryonic vesicles of the neural tube, which gives rise to the midbrain.

RHOMBENCEPHALON

One of the three primary embryonic vesicles of the neural tube, which gives rise to the hindbrain.

CELL AUTONOMY

A genetic trait in which only the genotype of the cell determines the corresponding phenotype. In contrast, a non-cell-autonomous phenotype is caused by the action of other cells on the cell of interest.

NEUREGULIN

Protein implicated in neural and muscular development. Among other functions, it stimulates the proliferation of Schwann cells and the rate of synthesis of nicotinic acetylcholine receptors in muscle.

HOMEOTIC TRANSFORMATION

The conversion of one body part into another due to mutations in a Hox gene.

RETINOIC ACID

A morphogen and regulator of differentiation during embryogenesis.

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Trainor, P., Krumlauf, R. Patterning the cranial neural crest: Hinbrain segmentation and hox gene plasticity. Nat Rev Neurosci 1, 116–124 (2000). https://doi.org/10.1038/35039056

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