Chromosome Traffic Cop
Before an egg becomes fertilized, chromosomes must pair up to pass along genetic information. This happens within each reproductive cell (eggs or sperm), when chromosomes of male and female origin move toward each other to eventually join.
University of Iowa biologists have discovered a protein that appears to regulate the speed at which the female (maternal) and male (paternal) chromosome strands move in order pair up. In laboratory tests, researchers saw the FKB-6 protein act like a brake on chromosome movement. Especially at the moment when chromosomes join to share DNA, critical to successful inheritance of parental genes.
The findings offer new insight into the intricate steps involved in animal fertility, from basic organisms to humans. It could also help biologists better understand defects that occur in reproduction, including those contributing to Down syndrome.
The research was published online this month in The Journal of Cell Biology.
"To our knowledge, this is the first study to show the importance of negative regulation of chromosome movement...and pairing between homologous chromosomes. This indicates that precise control of chromosome movement is imperative for the success of these processes," according to Sarit Smolikove, associate professor in biology and the paper's corresponding author.
Researchers identified a protein in nematodes (a type of worm) called FKB-6, which instructs another protein, dynein. By moving along filaments on each chromosome helps the pair of chromosomes move toward each other.
When the chromosome strands are joined, FKB-6 acts as a brake on dynein, slowing the process and ensuring the uninterrupted sharing of DNA.
"Chromosomes' movement is important because they need to move in synchronicity," Smolikove explains. "We've shown you don't want to move them too much or too frequently. You need to give the strands time to join for cell division to be done correctly."
Smolikove likens the process to a parent zipping a coat for a child. If the child is jerking about as the parent tries to zip the coat, it takes longer for the action to be completed; worse, the zipper could break, meaning the coat doesn't get zipped at all. Likewise, chromosome strands need to line up and have time to "zip up," correctly so genetic information is accurately swapped.
"There should be a balance between moving and stopping, and FKB-6 regulates those actions."
Sarit Smolikove PhD, Associate Professor, Department of Biology, University of Iowa, USA, and the paper's corresponding author.
Researchers screened some 200 proteins connected to meiosis (reproductive-cell division) in nematodes as they determined which ones were most involved in chromosome movement, focussing on the fusing stage.
They were able to determined FKB-6's role after they "knocked out" or canceled its function. This caused chromosome pairing to go haywire. Mutant chromosomes paused less, changed directions more, and traveled greater distances than ones with the FKB-6 protein intact.
Moreover, cells in worms without FKB-6 failed to properly perform mitosis, causing a high proportion of embryo defects.
Humans have a similar protein, FKBP52, which is also closely involved with stabilizing the filaments connecting chromosomes. Further testing will more precisely establish FKBP52's role in human reproduction.
In meiotic prophase I, homologous chromosome pairing is promoted through chromosome movement mediated by nuclear envelope proteins, microtubules, and dynein. After proper homologue pairing has been established, the synaptonemal complex (SC) assembles along the paired homologues, stabilizing their interaction and allowing for crossing over to occur. Previous studies have shown that perturbing chromosome movement leads to pairing defects and SC polycomplex formation. We show that FKB-6 plays a role in SC assembly and is required for timely pairing and proper double-strand break repair kinetics. FKB-6 localizes outside the nucleus, and in its absence, the microtubule network is altered. FKB-6 is required for proper movement of dynein, increasing resting time between movements. Attenuating chromosomal movement in fkb-6 mutants partially restores the defects in synapsis, in agreement with FKB-6 acting by decreasing chromosomal movement. Therefore, we suggest that FKB-6 plays a role in regulating dynein movement by preventing excess chromosome movement, which is essential for proper SC assembly and homologous chromosome pairing.
Benjamin Alleva, a graduate student in the department's Integrated Biology Graduate Program, is the paper's first author. Contributing authors include Nathan Balukoff and Amy Peiper, both of whom worked as undergraduates in Smolikove's lab.
The National Science Foundation funded the research through a three-year, $555,000 grant to Smolikove.
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Feb 1, 2017 Fetal Timeline Maternal Timeline News News Archive
University of Iowa biologists have found the FKB-6 protein appears to control
the speed at which maternal and paternal chromosome strands "pair up."
LEFT: FKB-6 protein present and chromosomes aligned and paired.
RIGHT: FKB-6 protein removed, reflected in few if any chromosome pairs.
Image Credit: Sarit Smolikove, University of Iowa