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Protein–Protein interactions, cytoskeletal regulation and neuronal migration

Nature Reviews Neuroscience volume 2, pages 408–416 (2001)Cite this article

Abstract

Neuronal migration, like the migration of many cell types, requires an extensive rearrangement of cell shape, mediated by changes in the cytoskeleton. The genetic analysis of human brain malformations has identified several biochemical players in this process, including doublecortin (DCX) and LIS1, mutations of which cause a profound migratory disturbance known as lissencephaly ('smooth brain') in humans. Studies in mice have identified additional molecules such as Cdk5, P35, Reelin, Disabled and members of the LDL superfamily of receptors. Understanding the cell biology of these molecules has been a challenge, and it is not known whether they function in related biochemical pathways or in very distinct processes. The last year has seen rapid advances in the biochemical analysis of several such molecules. This analysis has revealed roles for some of these molecules in cytoskeletal regulation and has shown an unexpected conservation of the genetic pathways that regulate neuronal migration in humans and nuclear movement in simple eukaryotic organisms.

Key Points

  • The analysis of human brain malformations has identified several genes required for neuronal migration during development, including doublecortin (DCX) and LIS1. Mutations in these genes cause a profound migratory disturbance known as lissencephaly ('smooth brain'), and recent studies have shown that they encode proteins that are important for cytoskeletal regulation.

  • Autosomal dominant and X-linked forms of lissencephaly have been identified. The LIS1 gene on chromosome 17 is responsible for a large percentage of the autosomal dominant forms, and doublecortin (DCX) is one of the genes responsible for X-linked lissencephaly. In males, DCX mutations produce lissencephaly phenotypes similar to those associated with LIS1 mutations. Heterozygous females show double cortex syndrome, in which a population of neurons arrests halfway between the cortex and the ventricle, forming a subcortical band in the white matter.

  • DCX is a microtubule-associated protein (MAP) that is expressed exclusively in postmitotic neurons and colocalizes with polymerized microtubules. DCX seems to stimulate polymerization and bundling of microtubules, properties that are disrupted by disease-causing mutations.

  • LIS1 encodes a ubiquitously expressed 45 kDa protein with 7 WD40 repeats, which are thought to mediate protein–protein interactions. LIS1 is reported to be a MAP that binds microtubules directly and it is thought to function in microtubule regulation in migrating neurons.

  • Insights into the microtubule-regulatory function of LIS1 have come from studies of its homologue, nudF, in the filamentous fungus Aspergillus nidulans. nudF mutations cause defects in nuclear migration, a microtubule-mediated event. Mutations in nudF and nudA, which encodes the heavy chain of cytoplasmic dynein, share a similar nuclear migration phenotype, and double mutations have the same phenotype as each single mutation. This suggests that dynein and nudF act in the same nuclear migration pathway. It is proposed that they function via destabilization of microtubules during nuclear migration.

  • The Aspergillus NUDE protein is thought to function as a downstream effector of NUDF in regulating nuclear migration. In mammals, two nudE homologues, mNudE and NUDEL, were cloned from LIS1 two-hybrid screens. They are similar in size and structural organization and both interact with LIS1 through a structurally similar amino-terminal region. mNudE interacts with multiple centrosomal proteins and might act as a structural and functional scaffold for the microtubule-organizing centre (MTOC). NUDEL binds directly to dynein and regulates its subcellular distribution. It is enriched in the processes of mature neurons, suggesting additional roles in axon transport and neurite outgrowth.

  • LIS1 physically interacts and forms complexes with dynein in mammals, and its overexpression induces spindle mis-orientation and mitotic arrest at M-phase, suggesting that LIS1–dynein interactions might be important for cell division. It is also suggested that LIS1–dynein interactions affect the translocation of the neuronal cell body during migration.

  • A model is proposed for LIS1- and DCX-mediated neuronal migration. Neurons receive migration signals and microtubules extend into the leading process. Then, LIS1 is modified and is recruited to the MTOC, where it binds to mNudE and/or NUDEL. This interaction reduces nucleation and polymerization of microtubules at the minus end, possibly by regulating the γ-tubulin complex. As a result, the microtubules shorten at the minus end and the nucleus is pulled towards the leading edge of the migrating neuron by microtubule-based motors, such as dyneins.

  • Other factors that underlie neuronal migration and might interact with the lissencephaly gene products have been identified. For example, the Cdk5 kinase is a candidate for regulating LIS1/DCX phosphorylation and function. Mutations in other genes, such as Reelin, Disabled, ApoE2R and VLDLR also cause defects in cortical neuronal migration. These all encode components of the Reelin signalling pathway, which has been implicated in regulation of the microtubule cytoskeleton.

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Figure 1: MRI appearance of human lissencephaly and double cortex syndrome.
Figure 2: Structure and domain organizations of DCX and other major microtubule-associated proteins.
Figure 3: Characteristic phenotype of Aspergillus nuclear distribution mutations.
Figure 4: Model for microtubule-based nuclear translocation in neuronal migration.

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Acknowledgements

The authors gratefully acknowledge the support of the National Institutes of Health. Research in the authors' laboratory was also supported by a grant from the March of Dimes.

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  1. Department of Neurology, Harvard Medical School, Beth Israel Deaconess Medical Centre, Harvard Institutes of Medicine, 4 Blackfan Circle, Boston, 02115, Massachusetts, USA

    Yuanyi Feng & Christopher A. Walsh

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DATABASE LINKS

LIS1

Lis1

DCX

tubulin

tau

MAP2

MAP4

MAP1A

MAP1B

DCAMKL1

PAFAH

Syk

dynein

dynactin

nudF

nudG

nudE

mNudE

NUDEL

MP43

Cdk5 kinase

P35

Reelin

Disabled

VLDLR

FLN1

FURTHER INFORMATION

Walsh Laboratory

Glossary

HYPOMORPHIC MUTATION

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.

PROJECTION DOMAIN

Microtubule-associated proteins are usually organized into two domains: the microtubule-binding domain and a projection domain. By electron microscopy, the projection domain can be seen as a filamentous arm extending from the wall of the microtubule; this arm can bind to membranes, intermediate filaments or other microtubules. Its length controls the spacing between microtubules.

CATASTROPHE

The abrupt transition of a microtubule — a dynamic polymer — from growing phase to shortening phase.

ORTHOLOGUES

Genes belonging to different organisms that carry out similar functions.

TWO-HYBRID SCREEN

A system used to determine the existence of direct interactions between proteins. It involves the use of plasmids that encode two hybrid proteins; one of them is fused to the GAL4 DNA-binding domain and the other one is fused to the GAL4 activation domain. The two proteins are expressed together in yeast and, if they interact, the resulting complex will drive the expression of a reporter gene, commonly β-galactosidase.

CELL CORTEX

The part of the microtrabecular lattice that lies under the cell membrane.

KINETOCHORE

Specialized assembly of proteins that binds to the centromeric region of the chromosome.

MINUS END

The end of the microtubule that anchors at the microtubule-organizing centre. It is also the end that assembles more slowly.

SURFACE PLASMON RESONANCE

An instrumental biosensor or device that detects alterations in the optical evanescent waves resulting from small changes in refractive index at the interface between the sample and the device. The instrument can measure biomolecular interactions in real time and allows the detailed analysis of the resultant signals.

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Feng, Y., Walsh, C. Protein–Protein interactions, cytoskeletal regulation and neuronal migration . Nat Rev Neurosci 2, 408–416 (2001). https://doi.org/10.1038/35077559

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