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  • Review Article
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Cell division

Asymmetric cell division during animal development

Nature Reviews Molecular Cell Biology volume 2, pages 11–20 (2001)Cite this article

Key Points

Summary

  • One mechanism for generating cellular diversity during development is to segregate cell-fate determinants predominantly into one daughter cell upon division. This review emphasizes the molecular parallels that are emerging for this process in different species.

  • In Caenorhabditis elegans, size asymmetry and segregation of cell-fate determinants during the first division of the zygote is mediated by the PAR proteins.

  • In the Drosophila central nervous system, neural precursors divide asymmetrically. Cell-fate determinants, including Miranda, Prospero and Numb, are localized to the basal cortex of neuroblasts during this division. The correlation between spindle orientation and crescent formation in neuroblasts is established by Inscuteable.

  • Homologues of PAR-3, atypical protein kinase C and PAR-6 mediate polarity in flies and mammals. In flies, they direct epithelial cell polarity and mediate both spindle orientation and localization of cell-fate determinants in neuroblasts. In vertebrates, this complex might polarize the actin cytoskeleton of epithelial cells by recruiting cdc42.

  • Other asymmetric divisions in the worm and the Drosophila peripheral nervous system are directed by extracellular cues that use the wingless receptor, Frizzled.

  • A common component for both intrinsically and extrinsically established asymmetry in worm, yeast and Dictyostelium might be heterotrimeric G proteins. In flies, this link is through the Inscuteable-binding protein Pins, which also contains binding domains for heterotrimeric G-protein α-subunits.

  • In worms and flies, localization seems to be an actin-dependent process. In flies, lethal(2) giant larvae is required for basal localization of cell-fate determinants in neuroblasts. It binds cytoplasmic myosin heavy chain, providing a direct link to the actin cytoskeleton.

  • There are homologues of many of these factors in mammals and growing evidence for a conserved role in the developing nervous system. For example, asymmetric localization of Numb and Notch homologues have been observed in mammalian nervous system stem cells.

Abstract

Although most cells produce two equal daughters during mitosis, some can divide asymmetrically by segregating protein determinants into one of their two daughter cells. Interesting parallels exist between such asymmetric divisions and the polarity established in epithelial cells, and heterotrimeric G proteins might connect these aspects of cell polarity. The discovery of asymmetrically segregating proteins in vertebrates indicates that the results obtained in invertebrate model organisms might also apply to mammalian stem cells.

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Figure 1: General concept for the orientation of asymmetric cell divisions.
Figure 2: Asymmetric cell division in the C. elegans zygote.
Figure 3: Asymmetric cell division in Drosophila neuroblasts.
Figure 4: Orientation of division in Drosophila neuroblasts.
Figure 5: Frizzled receptors direct asymmetric cell division in response to extracellular signals.
Figure 6: Function of heterotrimeric G proteins in cell polarity.
Figure 7: A potential mechanism for asymmetric cell division in vertebrate neural precursor cells.

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Acknowledgements

I thank all members of my laboratory, in particular M. Petronczki and M. Schaefer, for their contributions to the ideas presented here; M. Glotzer for valuable discussions that had considerable influence on this review; and J. -M. Peters and M. Glotzer for comments on the manuscript. Work in my laboratory is funded by Boehringer Ingelheim.

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  1. Research Institute of Molecular Pathology (IMP), Dr Bohr Gasse 7, Vienna, A-1030, Austria

    Juergen A. Knoblich

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DATABASE LINKS

PAR-3

PAR-6

PKC-3

PAR-2

PAR-1

Frizzled

Bazooka

Inscuteable

Prospero

Staufen

Miranda

Numb

PON

Cdc42

PINS

GoLoco domain

Pleckstrin homology domain

DLG

LGL

wingless

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G proteins

Glossary

ZYGOTE

Embryo at the one-cell stage between fertilization and the first cell division.

NEUROBLAST

Primary Drosophila neural precursor that gives rise to neural cells only. Divides asymmetrically in a stem-cell-like mode into another neuroblast and a ganglion mother cell.

SEVEN-TRANSMEMBRANE RECEPTOR

A class of receptors that contains seven membrane-spanning helices and usually transmits signals to the inside of a cell by activating heterotrimeric G proteins.

HETEROTRIMERIC G PROTEIN

A protein complex of three proteins (Gα, Gβ and Gγ). Whereas Gβ and Gγ form a tight complex, Gα is part of the complex in its inactive, GDP-bound, form but dissociates in its active, GTP-bound, form. Both Gα and Gβγ can transmit downstream signals after activation.

PDZ DOMAIN

Protein interaction domain that often occurs in scaffolding proteins and is named after the founding members of this protein family (Psd-95, discs-large and ZO-1).

RING FINGER

Protein domain consisting of two loops held together at their base by cysteine and histidine residues that complex two zinc ions. Many ring fingers function in protein degradation by facilitating protein ubiquitination.

GANGLION MOTHER CELL

(GMC) Small daughter cell of a neuroblast. Divides only once more to produce two neurons.

COILED-COIL DOMAINS

A protein domain that forms a bundle of two or three α-helices. Whereas short coiled-coil domains are involved in protein interactions, long coiled-coil domains forming long rods occur in structural or motor proteins.

SOP CELL

Sensory organ precursor cell that gives rise to all cells in a Drosophila sensory organ.

ORTHOLOGUE

The functional equivalent of a protein in another species.

TIGHT JUNCTIONS

Connections between individual cells in an epithelium that form a diffusion barrier between the two surfaces of an epithelium.

FRIZZLED

A protein family of seven-transmembrane receptors. Its founding member, frizzled, was identified as a so-called tissue polarity mutation in Drosophila that causes defects in the orientation of bristles and hairs. Frizzled proteins function as receptors for wingless and its vertebrate homologues, the Wnt proteins.

IMAGINAL DISCS

Epithelial sacs in Drosophila larvae that give rise to the tissues that later form the adult fly.

EPENDYMAL CELLS

A layer of cells that line the large fluid-filled cavities in the brain, the ventricles.

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Knoblich, J. Asymmetric cell division during animal development . Nat Rev Mol Cell Biol 2, 11–20 (2001). https://doi.org/10.1038/35048085

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