Comments on Mitotic Chromosome Motions
In spite of a series of ingenious experiments over the last 40 years,
the causes for most of the mitotic motions remains unclear.
The current paradigm in molecular biology requires that specific
molecules, and/or
molecular geometries, for force generation be identified. However, it
is possible to account for mitotic motions in terms of
experimentally known bound cellular electric charge distributions
on molecules interacting over nanometer distances.
This is the approach that has been
taken in the series of papers listed here.
The known charge in mitotic
chromosome motions resides at kinetochores, centrosomes, at the free ends
of microtubules, and on chromosome arms.
In 2002 Physical Review E and 2005 Journal of Electrostatics
papers (see above listing), I argued
that indirect experimental evidence indicates that
pole-facing "plates" of kinetochores manifest positive charge
that interacts with negative charge at and near the plus ends of
microtubules to generate force for poleward chromosome movements.
Subsequently, experiments have implicated positively charged molecules in
kinetochores in establishing a dynamic coupling to negatively charged
microtubule free ends for force generation during mitosis [Miller SA et al.,
Curr. Biol. 2008;18:1785].
Given positive charge at kinetochores, and negative charge at
and near the free plus ends of microtubules, it is possible to derive the
magnitude of the maximum (tension) force per microtubule for
poleward chromosome motions that falls within the experimental range
[Gagliardi LJ and Shain DH, Cell Div. 2016; 11:14; Gagliardi LJ and
Shain DH, Open J. Biophys., vol.9, 198-203 (2019)].
In the above-mentioned Phys. Rev. E and J.
Electrostat. papers I also proposed that indirect experimental
evidence is consistent with negative charge on centrosomes.
Experimental measurements have confirmed this [Hormeno S. et al.,
Biophys. J. 2009; 97:1022].
Experimental verification of net negative
charge on centrosomes is consistent with positive charge on free minus
microtubule ends for polar force generation. Positive charge on microtubule
minus free ends is supported by large
scale computer calculations on microtubules
[Baker NA et al., Proc. Natl. Acad. Sci. 2001; 98:10037].
A calculation of the polar
electrostatic poleward force per microtubule that
falls within the experimental range has been carried out
[Gagliardi LJ and Shain DH, Cell Div. 2014; 9:5].
Models in the current literature primarily
attempt to address one or two mitotic motions, most often involving
poleward force generation at kinetochores. Critical experiments involving
the "slip-clutch" mechanism [Rieder CL and Salmon ED, J. Cell Biol.
1994; 124:223;
Maiato H et al., J. Cell Sci. 2004; 117:5461], the effect of
calcium ion concentration on anaphase-A chromosome motion
[Zhang DH, Callaham DA, Hepler PK, J. Cell Biol.
1990; 111:171], antipoleward force production for chromosome congression
[Gagliardi LJ and Shain DH, Theor. Biol. Med. Model. 2014, 11:12],
and polar generation of poleward force
for chromosome motions are not consistently addressed by these models.
In the above listed papers,
interactions between known bound molecular charge
distributions can account for these observations.
Regarding molecular motor contributions to mitotic motions,
it is generally thought that molecular motors are likely
involved in the sliding microtubule sidewall "capture" motion of
chromatid pairs. The case for molecular motors as the cause for
post-attachment chromosome motions at kinetochores
is considerably less convincing.
Identifying the motive force is central to explaining post-attachment
chromosome motions
during mitosis. Presently, there is no consensus on what it is. I have
proposed a minimal assumptions model for
post-attachment chromosome movements based on the dynamic
instability of microtubules and nanoscale electrostatics.
Given the electrical properties of (tubulin and) microtubules, and
charge distributions on kinetochores, centrosomes and
chromosome arms,
as well as the pH-dependent dynamics of microtubules [Gagliardi LJ and
Shain DH, Theor. Biol. Med. Model. 2013,10:8],
it is possible to account for post-attachment prometaphase, metaphase,
and anaphase-A chromosome motions within a model
that also addresses the timing of these motions.