The spindle checkpoint is an integral regulator of chromosome segregation in

The spindle checkpoint is an integral regulator of chromosome segregation in CUDC-907 mitosis and meiosis. Preservation of fidelity in chromosome segregation in meiosis controlled by the spindle checkpoint also has significant impact in human health. This review highlights the contributions from meiotic systems in understanding the spindle checkpoint as well as the role of checkpoint signaling in controlling the complex divisions of meiosis. mice the univalents result in a checkpoint arrest. In some oocytes the sister kinetochores on the univalent chromosomes attach to opposite poles and achieve some level of “loose” alignment at the metaphase plate. After a substantial delay these oocytes and undergo anaphase onset [119]. Examination of the resulting MII oocytes indicate that checkpoint signaling is overridden when an average of 4 univalents remain that have not yet achieved bipolar attachment of sister kinetochores (Fig. 5E). Figure 5 Spindle checkpoint effectiveness in mouse oocytes during MI depends on the number of kinetochores that are unattached or lack bipolar tension. (A) Bipolar attachment of bivalent chromosomes allows normal timing of oocyte meiosis. (B) A high concentration … The above observations suggest that spindle checkpoint arrest in mouse oocytes requires strong checkpoint signaling from the combined output of several kinetochores lacking microtubule attachment and tension. Dilution of checkpoint signals in the large volume of oocyte cytoplasm likely contributes to the apparent reduced ability of oocytes to block progression in the presence of a small number of improperly attached chromosomes particularly in comparison to the stringent checkpoint signaling characteristic of spermatocyte meiosis or somatic cell mitosis. Meiotic aneuploidy and maternal age In humans meiotic aneuploidy is a major source of infertility miscarriage and congenital birth defects. The majority of meiotic aneuploidies in humans are due to errors in oogenesis. Combined data for detectable human trisomy after fertilization in humans indicates that most segregation errors occur during MI though a substantial fraction also occur in MII [120]. However analysis of first and second polar bodies obtained during in vitro fertilization therapy from women in their late 30’s or early 40’s reveals that anomalous events are common in both MI and MII [121 122 Most aneuploidies result in inviable embryos but some autosomal trisomies and some sex chromosome aneuploidies produce fetuses CUDC-907 that survive to term. It has long been recognized that the risk for trisomy rises sharply for women near the end of their reproductive lifespan [123]. Multiple genetic environmental and age-related factors likely contribute to the production of aneuploid gametes [124 125 The fact that most errors occur in oogenesis implicates the relaxed spindle checkpoint of oocytes as a potential contributing cause. Analysis of oocytes from older women has revealed diminished levels of message for several checkpoint proteins including Bub1 CUDC-907 BubR1 Bub3 and Mad2 [126 127 In at least some strains mouse oocytes from older mice also CUDC-907 show increased aneuploidy [128-130]. Mice engineered to express reduced levels of functional CUDC-907 checkpoint proteins BubR1 Bub1 and Mad2 exhibit increased oocyte aneuploidy and spindle defects [101 131 132 Older female mice also show lower levels of checkpoint message or protein expression in their oocytes or ovaries [128 131 Despite this evidence some studies have reported that oocytes from older mice do not exhibit a weaker spindle checkpoint since they do not show accelerated timing of anaphase onset in MI and they arrest when treated with the microtubule drug nocodazole [133 134 However a more recent RPLP1 study showed that oocytes from older females are significantly impaired in their ability to arrest anaphase onset when a low concentration of nocodazole is applied [135]. Kinetochores in oocytes from older mice have also been reported to show reduced ability to form stable bipolar attachments in MI [135 136 As discussed above mechanical tension from correct bipolar attachment is an important contributor to stabilizing kinetochore-microtubule attachment and to checkpoint silencing. The studies described may point to a general degradation of kinetochore function in oocytes of aged females that could contribute to higher rates of aneuploidy. Another proposed source of meiotic aneuploidy and its increased incidence with advanced maternal CUDC-907 age is.