Volume 5, Issue 4, October 2003, Pages 532–534
Open Archive
Abstract
Stem
cell self-renewal depends on their ability to divide asymmetrically,
with one daughter retaining stem cell identity. This often involves
precise orchestration of mitotic spindle orientation, but the machinery
used to ensure this outcome is understood in only a handful of examples.
In a recent issue of Science, Yamashita et al. provide new insights into the factors that control this process in the male germline of Drosophila, identifying roles for the centrosomal protein Centrosomin and tumor suppressor homologs of the APC family.
Main Text
Unlike
most characters in the news, stem cells live up to their hype. Stem
cells share the remarkable ability to undergo long-term self-renewal
while continuously generating differentiating daughters, allowing for
tissue maintenance and repair. To do so, they must divide
asymmetrically, with one daughter retaining the stem cell fate. Much of
the hype surrounds stem cells in a dish, but their secret lives within
our bodies remain poorly understood. Model organisms such as the fruit
fly Drosophila offer the opportunity to examine stem cell
behavior in vivo and to identify molecular players required for their
unique functions.
The mechanisms
by which asymmetric divisions are controlled are known in only a handful
of cases, with the best-characterized stem cells those of the Drosophila
central and peripheral nervous systems. The new paper from Yamashita et
al. provides another illuminating example. The Fuller lab and others
have focused on Drosophila spermatogenesis, making masterful
use of forward genetics to identify genes required for many aspects of
this process. Here they took an alternate approach, using cell
biological tools and reverse genetics to examine stem cell asymmetric
division.
Male germline stem cells form a rosette around a specialized set of somatic cells known as the hub (Figure 1A).
Using tubulin-GFP, they observed that stem cell mitosis is highly
polarized, with the spindle oriented perpendicular to the hub-stem cell
interface. One daughter thus remains attached to the hub and retains
stem cell identity while the other initiates differentiation as a
gonialblast. These fate differences are likely due to differing access
to stem cell-promoting signals from the hub (as discussed in Yamashita et al., 2003).
- Figure 1.Drosophila Centrosomin and APC Family Proteins Mediate Asymmetric Cell Division in the Male Germline(A) Schematic representation of the Drosophila male germline stem cells (GSC) surrounding the hub of somatic cells. In wild-type males, GSCs orient their centrosomes and spindles perpendicular to the hub-stem cell interface. Consequently, the daughter that remains in association with the hub retains the stem cell identity and the daughter that is displaced from the hub differentiates as a gonialblast (GB). A detailed view of the boxed area is shown in (B).(B) A model for asymmetric cell division in Drosophila male germline stem cells modified from Yamashita et al. (2003).(C) Schematic representation of the male germline stem cells in a cnn mutant germline. In these mutants, centrosome association with the cortex and spindle orientation are both disrupted. Consequently, some GSCs divide parallel to the hub, and both daughters retain stem cell identity. Therefore, cnn mutant germlines contain an increased number of GSCs.(D) In mammalian cells, APC proteins associate with the plus ends of microtubules at the cell cortex. A detailed view of the boxed area in the left panel is shown in the right panel.(E) In preblastoderm Drosophila embryos, APC2 acts with Armadillo and α-catenin to link mitotic spindles to cortical actin.
Yamashita
et al. determined that consistent spindle orientation is likely
facilitated by the consistent positioning of the centrosome; they
observed that one centrosome remains adjacent to the hub throughout the
cell cycle (Figure 1A).
To address the role of centrosomes in spindle orientation, they
examined males mutant for the integral centrosomal component Centrosomin
(Cnn). Cnn is essential for the formation of mitotic centrosomes.
Surprisingly, cells and flies can live without Cnn; mitotic spindles
form, albeit without astral microtubules, and spindles function
adequately in their absence (Megraw et al., 2001). Cnn is required for certain events, however, such as the rapid divisions in the early Drosophila embryo (reviewed in Raff, 2001), where astral microtubules appear to prevent spindle collision. The viability of cnn null males permitted Yamashita et al. to examine the male germline in the absence of functional mitotic centrosomes. In cnn
mutants, residual centrosomes (revealed by antibodies to γ-tubulin)
remained present during at least some portions of the cell cycle, but
both centrosome association with the cortex and the orientation of the
spindle perpendicular to the hub were disrupted (Figure 1C).
Any daughter continuing to contact the hub retained stem cell
character, so stem cell numbers increased. Thus, spindle orientation may
depend on the association of astral microtubules with a site on the
cell cortex near the hub.
