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Topic of the Month
Asymmetric
Cell Division
By Pamela J. Hines and Suzanne Kadereit
Asymmetric cell divisions are characteristic of any occasion when
the two daughters differ in fate, whether or not "stem cell"
is one of the fates. In the case of the stem cell, the cell's first
step must be to divide and to produce one daughter like itself,
able to continue as a stem cell, and one daughter unlike itself,
able to go down a path of differentiation.
Much insight has recently been gained regarding mechanisms underlying
asymmetric cell division in several different systems. The following
papers give a very brief overview about the latest developments
in this broadening field.
For asymmetric cell division, both intrinsic cell fate programs
and responses to extrinsic cues may be involved. In a thorough evolutionary
survey of germline stem cells in metazoans, Extavour and Akam find
that while in many model organisms preformation, a strategy using
inherited determinants, seems to prevail, the strategy of inductive
interaction is actually more often used, as for example in mammals.
Mechanisms of germ cell specification across the metazoans:
epigenesis and preformation. ABSTRACT
Extravour CG and Akam M (2003). Development 130:5869.
Examples of Intrinsic Determination:
Inherited determinants often direct fates of daughter cells, and
for these daughters' fates to differ, their suite of inherited determinants
must differ. A precursor to asymmetric cell division thus may be
establishment of polarity within one cell. Cellular polarity may
be stable, as in early embryos and perhaps in stem cells, or it
may be a transient feature of the cell, called on for specific purposes.
Polarity affects processes as diverse as bacterial chemotaxis, absorption
of nutrients at the intestinal epithelium, axon guidance and oogenesis,
as well as the generation of dissimilar daughter cells.
A recent example is presented by Haecker et al. who describe the
case in embryos of the small mustard-related plant Arabidopsis,
where proteins of the WOX family (relatives of homeobox genes) are
segregated at division of the zygote, with WOX2 going to the apical
daughter cell that will generate shoot and leaf tissues, and WOX8
to the basal daughter that will generate roots.
Expression dynamics of WOX genes mark cell fate decisions
during early embryonic patterning in Arabidopsis thaliana. ABSTRACT
Haecker A, Gross-Hardt R, Geiges B, Sarkar A, Breuninger H, Herrmann
M, Laux T (2004). Development Jan 7 [Epub ahead of print].
In the sensory organ precursor cell of Drosophila, asymmetric
localization of Frizzled, Strabismus and Prickle proteins define
two opposite domains before mitosis of the precursor cell. During
mitosis, Strabismus and Dishevelled proteins act in opposing fashions
on Partner of Inscuteable to promote the protein's asymmetric localization
at the anterior cortex of the precursor cell.
The planar cell polarity protein Strabismus promotes
Pins anterior localization during asymmetric division of sensory
organ precursor cells in Drosophila. ABSTRACT
Bellaiche Y, Beaudoin-Massiani O, Stuttem I, Schweisguth F (2004).
Development 131:469.
However, proteins are not the only subcellular components that may
be segregated asymmetrically. Lambert et al. show how mRNAs are
segregated in the mollusk Ilyanassa obsoleta by tagging along
with the centrosome.
Asymmetric inheritance of centrosomally localized mRNAs
during embryonic cleavages. ABSTRACT
Lambert, J. D., and Nagy, L. M. (2002). Nature 420:682.
And even the oxidative damage accumulated during the life cycle
of a cell can be distributed asymmetrically during cell division
to spare the daughter cell, with carbonylated proteins remaining
in the mother cell.
Asymmetric inheritance of oxidatively damaged proteins
during cytokinesis. ABSTRACT
Aguilaniu, H., Gustafsson, L., Rigoulet, M., and Nystrom, T. (2003).
Science 299:1751.
There may also be other sorts of cues that direct daughter cells to
different fates. In the case of Volvox, an asymmetric cell division
generates cells different only by size, and then by as yet unknown
mechanisms the size of the daughter cell leads to activation of either
a somatic or germline program.
Differentiation of germinal and somatic cells in Volvox
carteri. ABSTRACT
Schmitt R. (2003). Curr Opin Microbiol 6:608.
The question now becomes how all these molecules are distributed
in an unequal fashion within the cell. In recent years much progress
has been made regarding the shuttling of molecules through the cytoplasm.
The cytoplasm, once believed to be a "liquid soup" filling
the cell, is now seen to include a sophisticated railway system
of microtubules on which molecules are moved in different ways to
their destination.
No surprise, then, that the microtubule system is critical for
asymmetric cell division and distribution of molecules within the
cell. Kusch et al. give an overview about how the spindle and microtubules,
as well as certain highly conserved proteins, effect asymmetric
division of cells.
Spindle asymmetry: a compass for the cell. ABSTRACT
Kusch, J., Liakopoulos, D., and Barral, Y. (2003). Trends Cell Biol
13:562.
Considerable research is now directed towards identifying the molecules
that signal and enact asymmetry initiated by determinant factors.
For example, progress into understanding how the eukaryotic cell
spindle is positioned implicates the Dryk family kinases in C.
elegans embryos.
The minibrain kinase homolog, mbk-2, is required for
spindle positioning and asymmetric cell division in early C. elegans
embryos. ABSTRACT
Ming Pang K, Ishidate T, Nakamura K, Shirayama M, Trzepacz C, Schubert
CM, Priess JR, Mello CC (2004). Dev Biol 265:127.
Another example is shown by Barros et al., implicating the movement
of nonmuscle myosin II during mitosis in the asymmetric partitioning
of determinants in the Drosophila neuroblast.
Drosophila nonmuscle myosin II promotes the asymmetric
segregation of cell fate determinants by cortical exclusion rather
than active transport. ABSTRACT
Barros, C. S., Phelps, C. B., and Brand, A. H. (2003). Dev Cell
5:829.
The bacterium Caulobacter presents yet a different strategy for
differentiating the soon-to-be-daughter cytoplasmic compartmentsfluorescence
microscopy shows that shortly before actual cell division occurs,
the Caulobacter cytoplasm is divided by cytoplasmic diffusion barriers
into two compartments that only then begin to reorganize their contents,
removing the CtrA master regulator protein from one of the compartments.
Fluorescence bleaching reveals asymmetric compartment
formation prior to cell division in Caulobacter. ABSTRACT
Judd EM, Ryan KR, Moerner WE, Shapiro L, McAdams HH (2003). Proc
Natl Acad Sci U S A. 100: 8235.
Another mechanism occurs in Drosophila follicle cells and
oocytes, where phosphorylation status of a critical protein regulates
whether it does or doesn't get localized to the cellular apex, thus
organizing apical-basal polarity for the cell.
Drosophila PAR-1 and 14-3-3 inhibit Bazooka/PAR-3 to
establish complementary cortical domains in polarized cells. ABSTRACT
Benton R and Johnston DS (2003). Cell 115:691.
Although asymmetrical cytokinesis seems to require considerable
attention from the cell, middle-of-the-road symmetrical cytokinesis
is not necessarily a default. Howard et al., studying the rod-shaped
bacterium Bacillus subtilis, propose that localization of certain
proteins to each pole, in part because of the increased cell surface
curvature at the poles, serves to exclude the cell division apparatus
from the poles, thus leaving no choice but for cytokinesis to take
the middle of the cell.
A mechanism for polar protein localization in bacteria.
ABSTRACT
Howard M (2004). J Mol Biol 335:655.
Examples of Extrinsic Influences:
As mentioned in the beginning, the strategy of inductive signaling
from surrounding tissues is a mechanism frequently used to direct
asymmetric division. A good example are the stem cell niches in
the Drosophila testes and ovaries.
In the testes, cells that retain a physical attachment to the hub,
a cluster of somatic cells, also retain identity as stem cells.
Those cells that cytokinesis places away from the hub, without physical
attachment, are launched off into the big wide world of spermatogenesis.
Yukiko et al. add to this picture by showing that the stem cell
uses the APC tumor suppressor protein to orient the mitotic spindle
perpendicular to the hub, thus ensuring a cell division that will
place one daughter near, and one daughter away from, the hub.
Orientation of asymmetric stem cell division by the
APC tumor suppressor and centrosome. ABSTRACT
Yamashita, Y. M., Jones, D. L., and Fuller, M. T. (2003). Science
301:1547.
In the Drosophila ovaries, the germline stem cell also maintains
contact with the niche and maintains high levels of Dpp signaling.
Chen and McKearin show that Dpp signaling directly results in repression
of expression of the bam gene and maintenance of the stem
cell, whereas the daughter cell dissociates from the niche, looses
Dpp signaling and repression of the bam gene expression,
and can thus start to differentiate.
Dpp signaling silences bam transcription directly to
establish asymmetric divisions of germline stem cells. ABSTRACT
Chen D and McKearin D (2003). Curr Biol 13:1786.
Research into asymmetric cell division has recently exploded and
the described mechanisms are more than abundant. And although we
have only covered part of the topic, we hope to have provided sufficient
food for thought for anybody inquiring into how stem cell self-renewal
might be regulated.
For readers in need of URLs for the listed articles:
Aguilaniu, H., Gustafsson, L., Rigoulet, M., and Nystrom, T. (2003):
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12610228&dopt=Abstract
Barros, C. S., Phelps, C. B., and Brand, A. H. (2003):
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14667406&dopt=Abstract
Bellaiche Y, Beaudoin-Massiani O, Stuttem I, Schweisguth F (2004):
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14701683&dopt=Abstract
Benton R and Johnston DS (2003). Cell 115:691.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14675534&dopt=Abstract
Chen and McKearin (2003):
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14561403&dopt=Abstract
Extravour CG and Akam M (2003):
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14597570&dopt=Abstract
Haecker A, Gross-Hardt R, Geiges B, Sarkar A, Breuninger H, Herrmann
M, LauxT (2004):
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14711878&dopt=Abstract
Howard M (2004):
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14672671&dopt=Abstract
Judd EM, Ryan KR, Moerner WE, Shapiro L, McAdams HH (2003):
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12824468&dopt=Abstract
Kusch, J., Liakopoulos, D., and Barral, Y. (2003):
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14573349&dopt=Abstract
Lambert, J. D., and Nagy, L. M. (2002):
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12478296&dopt=Abstract
Ming Pang K, Ishidate T, Nakamura K, Shirayama M, Trzepacz C, Schubert
CM, Priess JR, Mello CC (2004):
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14697358&dopt=Abstract
Schmitt R. (2003):
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14662357&dopt=Abstract
Yamashita, Y. M., Jones, D. L., and Fuller, M. T. (2003):
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12970569&dopt=Abstract
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TOM Archives
Updated: March 18, 2004
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