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Bone morphogenetic protein signalling and vertebrate nervous system development

Key Points

  • Signalling from bone morphogenetic proteins (BMPs), which are members of the transforming growth factor-β protein family, is crucial for the development of both the central and peripheral nervous systems in vertebrates.

  • BMPs act at different stages of neural development and in different regions of the CNS to regulate cell fate, proliferation and differentiation. The development of the CNS begins with the specialization of the ectoderm into either non-neural or neural ectoderm, a transformation that is actively directed by the presence or absence of BMP signalling, respectively.

  • BMPs help to define the region from which a vertebrate-specific population of neural cells, the neural crest, will be generated. The neural crest arises at the border between the neuroectoderm and the non-neural ectoderm and gives rise to many diverse cell populations, including the PNS, melanoctyes and head skeletal elements.

  • BMP signalling positively regulates CNS development at later stages of development. As the neural tube closes, BMP proteins secreted from the ectoderm and the signalling centre at the dorsal-most region of the CNS, the roof plate, are important for patterning of the CNS. BMP signalling patterns the dorsal and intermediate regions of the spinal cord. Furthermore, active repression of BMP signalling is also crucial for the normal patterning of the ventral spinal cord.

  • BMP proteins are implicated in the regulation of axonal projections; in particular, in the repulsion of commissural axons from the dorsal aspect of the neural tube.

  • BMPs are negative regulators of proliferation and cell survival in the brain, which is the opposite of their effects in the spinal cord. BMPs also downregulate the expression of the anterior forebrain markers brain factor 1 (Bf1), fibroblast growth factor 8 (Fgf8) and sonic hedgehog (Shh). In addition, BMPs are important regulators of cerebellar granule neuron fate determination.

  • In a Smad-independent process, BMP signalling activates the LIM-domain-containing protein kinase 1 (LIMK1), which regulates the actin cytoskeleton and leads to changes in dendrite morphogenesis and the stabilization of synapses.

Abstract

Transforming growth factor-β (TGFβ) signalling, particularly signalling from the bone morphogenetic protein (BMP) members of this protein family, is crucial for the development of both the central and peripheral nervous systems in vertebrates. Experimental embryology and genetics performed in a range of organisms are providing insights into how BMPs establish the neural tissue and control the types and numbers of neurons formed. These studies also highlight the interactions between different developmental signals that are necessary to form a functional nervous system. The challenges ahead will be to uncover functions of TGFβ signalling in later stages of CNS development, as well as to determine possible associations with neurological diseases.

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Figure 1: Bone morphogenetic protein (BMP) receptors mediate BMP signalling by activating Smad transcription factors.
Figure 2: Formation of the neural tube by neurulation.
Figure 3: The spinal cord is patterned along its dorsoventral axis.
Figure 4: Expression of bone morphogenetic proteins in the brain.

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Acknowledgements

We thank K. Artinger, L. Sussel and I. Zohn for critical reading of the manuscript. We gratefully acknowledge all individuals who have contributed to this field and apologize to those who were not included in this review due to space limitations. L.N. is an Investigator of the Howard Hughes Medical Institute.

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Correspondence to Lee A. Niswander.

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DATABASES

Entrez Gene

BMP4

BMP7

BMPRIA

BMPRIB

BMPRII

chordin

gremlin

LIMK1

Math1

Msx1

NGN1

Nkx2.2

noggin

Pax3

Pax6

Pax7

SHH

Wnt3a

Zic1

ZFIN

one-eyed pinhead

snh

sbn

swr

Glossary

EXPRESSION CLONING

A function-based gene discovery method. In Xenopus spp., this is done by injecting mRNA of candidate genes into the egg or early embryo and screening for a phenotype of interest: for example, the formation of a secondary body axis or the loss of head structures.

MORPHOLINO

A non-ionic DNA analogue of 25 nucleotides. When targeted to the 5′ untranslated region or start codon, a morpholino may prevent the translation of its target mRNA, generating a partial loss-of-function phenotype.

EMBRYONIC ORGANIZER

(Also known as Spemann's organizer.) Originally defined as the tissue in the gastrulating embryo that has the potential to induce a secondary body axis when grafted ectopically. Now it is recognized as an important signalling centre that regulates the basic body plan through the action of various signalling molecules, including antagonists of BMP.

EPIBLAST

The layer of a blastula that gives rise to the ectoderm after gastrulation.

SMALL INTERFERING RNA

(siRNA). A sequence-specific gene-silencing tool used in RNA interference. siRNAs are short fragments of synthetic double-stranded RNA with 21–23 pairs of nucleotides that have sequence specificity to the gene of interest (the target). These small double-stranded RNAs trigger degradation of the target RNA, thereby creating a partial loss-of-function by decreasing the amount of translatable RNA. As such, siRNA can reveal the requirement for the gene of interest in targeted cells.

HEDGEHOG SIGNALLING

Hedghog (HH) is a family of secreted proteins that regulate key developmental processes in both vertebrates and invertebrates through a receptor-mediated signalling cascade. In the vertebrate CNS in particular, HH proteins, especially sonic hedgehog, have many roles, including ventral patterning, axon guidance, cell survival and differentiation.

SERUM-FREE MOUSE EMBRYO CELLS

(SFME cells). A cell line derived in a defined serum-free medium. These cells have been cultured for more than 200 generations and show properties of neural progenitor cells.

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Liu, A., Niswander, L. Bone morphogenetic protein signalling and vertebrate nervous system development. Nat Rev Neurosci 6, 945–954 (2005). https://doi.org/10.1038/nrn1805

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