Telephone: (856) 489-4057
gagliard@camden.rutgers.edu
[4.] Microscale Electrostatics in Mitosis, Journal of Electrostatics,
vol. 54, 210-232 (2002).
Comments on current research
In spite of a series of ingenious experiments over the last 20 - 25 years,
the cause for many of the mitotic
motions remains unclear. The
expectation of many researchers in the field had been that molecular
motors would eventually be shown to be the motive force for
chromosome motions. This may be changing. Several new models
have been proposed recently that are either electrostatic in nature
or leave the precise mechanism for force generation unspecified
in a simulation that introduces a number of adjustable parameters.
The current paradigm of molecular biology requires that specific molecules,
or molecular geometries, for force generation be identified. However, it
is possible to account for mitotic motions in terms of
experimentally known cellular electric charge distributions interacting
over nanometer distances without having specific molecules in mind.
This is the approach that I have
taken in the series of papers listed here.
Chromosome motions can be described in terms
of electric charge distributions. The known charge in mitotic
chromosome motions is the net charge
at the ends of microtubules, on chromosome arms,
and on centrosomes and kinetochores.
In a 2005 paper, I argued that indirect experimental evidence indicates
that there is a net positive charge on kinetochores (see reference [2]
above, p. 316). Assuming this charge, and the known negative charge at
the free plus ends of microtubules, it was possible to derive a
magnitude of the maximum (tension) force per microtubule for
poleward chromosome motions that falls within the experimental range.
A major advantage of this
approach is that it appears to offer the possibility of discovering a
minimal assumptions comprehensive model for post-attachment chromosome
motions.
A model of this sort can point the way to the eventual
discovery of specific molecules, and their biochemistries, that are
responsible for the various mitotic motions.
This is what has happened.
Recently, a number of experiments have shown that kinetochore molecules
that bind with microtubules
have a net positive charge and that poleward force for chromosome motions
may be due to electrostatic interactions between these molecules and
negative charge on microtubules. These discoveries might have been made
sooner
if the above mentioned paper (available on line 5 November 2004) had been
duly noted.
As mentioned above, several new,
fundamentally electrostatic, models have been advanced recently involving
certain molecules and their interactions.
As in the situation involving models that center partially or wholly on
simulations, these approaches are quite complex in their assumptions and
primarily attempt to address one or two mitotic motions, most notably
poleward force generation at kinetochores. Critical experimental
observations such as the "slip-clutch" mechanism [Maiato et al., 2004],
observations of calcium ion concentration on anaphase-A
chromosome speeds [Zhang et al., 1990], and polar generation of force
for poleward chromosome motions are not addressed.
[ Maiato H., DeLuca J., Salmon E.D., Earnshaw W.C. 2004. J. Cell Science,
vol. 117, p. 5461. ]
This is to be contrasted with the
minimal assumptions comprehensive model for post-attachment chromosome
motions presented in the series outlined here.
[ Zhang D.H., Callaham D.A., Hepler P.K. 1990. J. Cell Biol.,
vol. 111, p. 171. ]
Regarding molecular motor contributions to mitotic motions,
it is generally thought that molecular motors are likely to be
involved in the sliding microtubule sidewall "capture" motion of
chromatid pairs. The case for molecular motors as the cause for
post-attachment chromosome motions is considerably less convincing.
As discussed above, identifying the motive force is central to explaining
chromosome motions
during mitosis. Presently, there is no consensus on what it is. I have
proposed a minimal assumptions model for the dynamics of
post-attachment chromosome motions based on nanoscale electrostatics.
Given the electrical properties of tubulin (and thus microtubules),
charge distributions on kinetochores, centrosome matrices, and
chromosome arms,
it is possible to account for prometaphase post-attachment,
metaphase, and anaphase chromosome motions within a comprehensive model
that addresses all of the following in a unified manner:
(See above links to numbered references. Page numbers in references 1
and 3 refer to the preprint versions linked to
this website, and differ from the actual page numbers in the Journal
of Electrostatics and Physical Review E papers.)
1. Efficiency of aster and spindle assembly and the motive force for the
motion of asters and forming spindles
( [4], p.222 ).
2. Chromatid pair attachment ( [3], p. 12 ).
3. Motion of monovalently attached chromatid pairs ( [2],
pp. 320 & 321; [3], pp, 12 & 13 ).
4. Motion of bivalently attached chromatid pairs; congression ( [2],
pp. 321 & 322; [3], pp. 13 & 14 ).
5. Metaphase chromatid pair oscillations ( [2], p.322; [3], pp. 14 & 15 ).
6. Anaphase-A chromosome motion ( [1], pp. 19-21; [2], pp. 322 & 323 ).
7. Anaphase-B pole separation ( [1], pp. 21 & 22; [4], pp. 228-230 ).
8. An ab initio theoretical calculation of the maximum tension force
exerted by a microtubule during mitosis that falls
within the experimental range ( [1], pp. 16-18; [2], pp. 315-318 ).
9. Poleward force generation at poles with associated microtubule flux
is explained by the same microtubule nanoscale
electrostatic disassembly force as at kinetochores ( [1], [2] ).
10. The timing and sequencing of the above motions (Book, Chapter 5;
also see Chapter 5 Summary for a capsule version). The book also offers
my latest on items 1 through 9 above.