Kinetochore orientation

Salmon ED. Merotelic kinetochore orientation is a major mech- 53. anism of aneuploidy in mitotic mammalian tissue cells. J. Cell. 

Cimini, D., Howell, B., Maddox, P., Khodjakov, A., Degrassi, F., Salmon, E. D. (2001). Merotelic kinetochore orientation is a major mechanism of aneuploidy in mitotic mammalian tissue cells. The Journal of Cell Biology, 153, 517—527. 

McIntosh et al. (1969) formulated equally specific hypotheses for the events before metaphase and for those in telophase which will not be considered in detail. Some apparent problems with their proposals for prometaphase congression and kinetochore orientation are noted elsewhere (pp. 243-244 266). 

Three fundamental principles have been known for some time and these underlie all further analysis 1. The distribution of chromosomes is determined by kinetochore orientation—the association of a kinetochore with a particular pole by chromosomal spindle fibers. Thus the chromosome moves in anaphase to that pole, and the usual equipartition of chromosomes occurs because the partner half-bivalents comprising each bivalent are oriented to opposite poles—orientation (see Fig. 11). 2. Kinetochore orientation is established during prometaphase. Already suggested by studies of fixed material, this was conclusively documented in living cells by Dietz (1956). 3. The initial orientation established at the start of prometaphase is often inappropriate. For example, in crane fly meiosis, 10 percent of the bivalents initially shows unipolar orientation (Bauer et al., 1961), i.e., both half-bivalents are oriented to the same pole (see Fig. 11). Nondisjunction and abnormal chromosome complements would inevitably ensue if such... 

Granted that the proposed explanation is at least reasonable for both meiotic and mitotic chromosome distribution, can the fundamental difference between these divisions also be explained As Ostergren (1951) proposed, a kinetochore structural difference may parallel the kinetochore orientation difference. An opposite polarity of sister kinetochores in mitosis has just been invoked to explain, in part, achievement of bipolar amphiorientation. On the same assumptions, if sister kinetochores lie close together and have a common polarity, their orientation to the same pole (syntely) should at least be facilitated. The required polarity occurs in the one example studied at late prophase (Amphiuma, p. 267). 

Church K. and Lin H.P.P. 1982. Meiosis in Drosophila melanogaster. The prometaphase-1 kinetochore microtubule bundle and kinetochore orientation in males. J. Gell Biol. 93 365-373. 

Loss of sister chromatid cohesion would therefore be sufficient for the sudden movement of chromatids to opposite poles at the metaphase to anaphase transition. According to this hypothesis, a specific apparatus binds chromatids together during replication, holds them in an orientation that facilitates the attachment of sister kinetochores to spindles extending to opposite poles, and resists the splitting force that results from this bipolar attachment to the spindle. Destruction of this specialized cohesive structure triggers movement of chromatids to opposite poles at the onset of anaphase. 

Goldstein LS 1981 Kinetochore structure and its role in chromosome orientation during the first meiotic division in male D. melanogaster. Cell 25 591-602... 

M.J. Stark, K. Nasmyth, Evidence that the Ipll-Slil 5 (Aurora kinase-INCENP) complex promotes chromosome bi-orientation by altering kinetochore-spindle pole connections. Cell 2002, 108, 317-329. 

PROMETAPHASE. No entirely satisfactory hypothesis of prometaphase congression is available. The chief issues are the extent to which poleward forces are responsible and, of course, the mechanism of force production or regulation which produces a stable chromosome position midway between the poles. Consideration of the force equilibrium hypothesis of Ostergren (summary 1950 see also Rashevsky, 1941 and Ostergren et al., 1960) illustrates the problems. The hypothesis postulates, first, poleward forces at the kinetochores of each chromosome (or bivalent). If these kinetochores are oriented to... 

The proportion of bivalents that achieve bipolar orientation in this fashion will doubtless vary in cells from different organisms. Thus the proportion may be lowered if long bivalents occur and their interkinetochoric chromatin is flexible. Such bivalents are often observably flexed between the kinetochores of partner half-bivalents, which are therefore not constrained to face in opposite directions. As expected from the present interpretation of initial orientation, these bivalents malorient abnormally often (Ostergren, 1951, pp. 140 ff White, 1961 Henderson et al., 1970). Conversely, in cells where individual spindles form around each chromosome and are oriented to each... 

Fig. 13. Repeated experimental induction of unipolar malorientation in one bivalent of a living grasshopper Melanopius differentiaHs) spermatocyte. The kinetochoric ends of the micromanipulated bivalent are identified by numbered arrows, and the time in minutes is indicated on each print. The micromanipulation needle was removed from the cell after each induction of unipolar orientation (25, 33.6, 52, and 157 minutes), and natural reorientations to the normal bipolar orientation followed in every case (33.0, 40.0, 94, and 211 minutes). A normal anaphase ensued (263, 284 minutes). Details In the text. XI,000. (From Nicklas. 1967. Chromosoma, 21 17-50.)...

A. Most bivalents achieve bipolar orientation immediately because 1. individual half-bivalents tend to orient to the pole they most nearly face and 2. chromosome structure is such that if one half-bivalenf s kinetochores face one pole, those of its partner face the opposite pole. 

This meiotic orientation sequence is the rule for forms with localized kinetochores, but the reverse sequence also occurs (reviewed by Rhoades, 1961 John and Lewis, 1965). 

Only some unpaired half-bivalents amphiorient, and this variation may well seem puzzling. Briefly, a probable explanation is that on Ostergren s (1951) hypothesis, metiotic versus mitotic orientation depends upon the same factors involved in initial orientation the position of kinetochores relative to each other and preferential orientation. As has been seen, initial orientation is not errorless, because chromosomes may by chance lie in positions making appropriate orientation of their kinetochores more or less unlikely. Hence, amphiorientation of ha -bivalents may be viewed as an enor, especially likely when univalency induces frequent reorientation (see p. 272) and the half-bivalent is exposed repeatedly to the hazard of amphiorientation which may be possible whenever the half-bivalent s kinetochores happen to lie perpendicular to the spindle axis during reorientation. 

Exactly this is observed in studies on fixed cells (reviewed by John and Lewis, 1965, pp. 52ff.) and following experimental destruction of the linkage by micromanipulation of living cells (Nicklas, unpublished). A more exact prediction is possible from the postulated role of bipolar tension in reorientation unpaired meiotic chromosomes that retain the meiotic synorientation of both sister kinetochores to the same pole should be unstable and frequently reorient. If, however, they achieve amphiorientation, as do mitotic chromosomes, a stable bipolar orientation should result. Both conditions occur in nature and with the expected result (living cells with unpaired sex chromosomes, Dietz, 1956 Bauer et al., 1961 Nicklas, 1961 fixed cells, reviewed by John and Lewis, 1965). 

The distribution of chromosomes in meiosis is understandable in terms of initial orientation and reorientation. Direct evidence that initial orientation and reorientation are now explained at the cytological level comes from experiments on bivalents in which orientation and distribution are predictably altered the experimenter 1. can determine the distribution of any chosen chromosome 2. can induce unstable malorientation and 3. can stabilize malorientations and induce nondisjunction. The explanation offered is easily extended to chromosome distribution in mitosis and to most units other than bivalents in meiosis. Testable molecular hypotheses are readily suggested. These would relate features of the cytological explanations to the generally documented organizing center activity of kinetochores and to spindle fiber lability. 

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