Growth, Differentiation and Sexuality

cytial divisions during Drosophila embryogenesis,
damaged nuclei are simply discarded and do not
contribute to subsequent generations.
IX. Regulation of Mitosis in Response
to Spindle Damage
The spindle checkpoint arrests mitosis if a properly
assembled bipolar spindle is not present. The
checkpoint also becomes operative if chromosomes
do not properly attach to an assembled spindle.
A complex of proteins, including Bub1-Bub3 and
Mad1-Mad3, detect spindle abnormalities and trigger
checkpoint activation, which ultimately results
in inhibition of APC activation (Lew and Burke
2003). As a result, mitosis cannot proceed past the
metaphase-to-anaphase transition because sister
chromatids remain attached.
Limited genetic analyses in A. nidulans highlight
the existence of the spindle checkpoint in filamentous
fungi, and suggest that it is organized in
a manner similar to yeast and animal cells. The A.
nidulans homologues of Bub1 and Bub3, SldA and
SldB, respectively, were identified in a screen for
mutantsthatcouldnottoleratelossofdyneinfunction
(Efimov and Morris 1998). Characterization of
sldA and sldB mutants revealed phenotypes consistent
with a defective spindle checkpoint, including
loss of viability when spindle assembly is compromised.
In addition, a homologue of Mad2 has been
implicated in the A. nidulans spindle checkpoint
response (Prigozhina et al. 2004). Notably, the latter
study uncovered a possible role for γ-tubulin in
the spindle checkpoint, where it may facilitate the
formation of an SPB-associated complex that detects
spindle abnormalities and halts mitosis. Another
recent study suggested that telomeres could
also mediate spindle checkpoint function (Pitt et al.
2004). In particular, mutations affecting NimU, the
A. nidulans homologue of the telomere-binding
protein Pot1, permit mitotic progression in the
presence of spindle defects. Despite this progress,
a coherent picture of the spindle checkpoint in filamentous
fungi has yet to emerge. One interesting
issue that warrants investigation is whether a single
detached chromosome in one nucleus can arrest
the propagation of a “parasynchronous” mitotic
wave. Presumably, the affected nucleus would
become refractory to the wave and would not divide.
However, segregation of detached chromosomes
may be tolerated in a multinucleate cell, as
Fungal Mitosis 47
it could provide a mechanism for chromosome exchange
during the parasexual cycle.
X. Future Challenges
Considerable progress has been made toward understanding
the regulation of mitosis in filamentous
fungi. Important insights into the mechanisms
that regulate mitotic entry have been obtained. In
addition, the mode by which DNA damage checkpoint
signals impinge upon the mitotic regulatory
network has been described. Nevertheless, key
questions remain unanswered. In many cases, these
questions reflect unique features of fungal biology
that must be taken into account to understand mitosis
and its coordination with other components
of the duplication cycle. Several of the more significant
questions are discussed below.
A. What Is the Critical Function of NimA
in the Regulation of Mitotic Entry?
NimA is clearly required for multiple functions that
promote mitotic entry in A. nidulans,andpresumably
other filamentous fungi. Although these functions
include chromosome condensation and spindle
organization, recent results suggest that regulation
of nuclear transport may be the most important
downstream effect (De Souza et al. 2004).
If so, this would provide a potential explanation
for why NimA is essential for mitotic entry in filamentous
fungi, but not animal cells. Because the
nuclear envelope does not break down, regulated
nuclear transport may allow the rapid accumulation
of CDKs and other factors at the G2/M transition.
This may be particularly important for propagation
of the parasynchronous mitotic wave in
multinucleate hypha cells.
B. How Is Mitotic Exit Coordinated
with Cytokinesis?
The mechanisms underlying mitotic exit in filamentous
fungi remain to be determined. Furthermore,itisnotknownhowcytokinesisiscoordinated
with the completion of mitosis (Wendland
and Walther, Chap. 6, this volume). In animal cells,
the spindle mid-zone appears to play a key role
in the spatial and temporal regulation of cytokinesis.
However, although the mitotic spindle regulates
septum formation in A. nidulans (Momany