Impaired cell division leads to neuronal disorder

Prof. Erich Nigg and his research group at the Biozentrum of the University of Basel have discovered an amino acid signal essential for error-free cell division. This signal regulates the number of centrosomes in the cell, and its absence results in the development of pathologically altered cells. Remarkably, such altered cells are found in people with a neurodevelopmental disorder, called autosomal recessive primary microcephaly. The results of these investigations have been published in the current issue of the US journal “Current Biology”.

Cell division is the basis of all life. Of central importance is the error-free segregation of genetic material, the chromosomes. A flawless division process is a prerequisite for the development of healthy, new cells, whilst errors in cell division can cause illnesses such as cancer. The centrosome, a tiny cell organelle, plays a decisive role in this process.

Prof. Erich Nigg’s research group at the Biozentrum of the University of Basel has investigated an important step in cell division: the duplication of the centrosome and its role in the correct segregation of the chromosomes into two daughter cells. The protein STIL has an essential function in this process. It ensures that centrosome duplicate before one half of the genetic material is transported into each of the two daughter cells.

KEN-Box important for protein breakdown

During cell division, the protein STIL is degraded. If this does not occur, the protein accumulates in the cell, which then causes an overproduction of centrosomes. As a consequence, mis-segregated chromosomes are incorporated into the daughter cells, which then represent cells with faulty genetic material. The scientists discovered an amino acid signal on the STIL protein, a so-called KEN-Box, and showed that this is critical for the breakdown of the protein: “The Ken-Box is the signal that orders the protein degradation machinery to break down the STIL protein,” explains Christian Arquint, the first author of this publication. In the absence of the KEN-Box, the protein is not degraded.

Absence of the KEN-Box causes microcephaly

In some patients with microcephaly, a neuronal disorder that leads to a reduced number of nerve cells being produced and, therefore, a smaller brain, the KEN-box is lacking from the STIL protein. The scientists were thus able to demonstrate a tantalizing connection between the absence of this particular amino acid signal and an illness. “When during our investigations of cell division and centrosome duplication we came across a connection to the disorder microcephaly, we were particularly pleased, as this helps us to better understand how this disorder develops“, says Christian Arquint.

In the future, the research group led by Erich Nigg plans to uncover other connections between errors of cell division and the illness microcephaly. They also want to focus on the investigation of other proteins that play important roles in the process of cell division, in particular those involved in centrosome duplication.

SOURCE: Wellcome Images, B0007805 Sperm cell
Digital artwork/Computer graphic by Anna Tanczos

The male gamete

Each single spermatozoan (plural spermatozoa) contains a haploid number of chromosomes (one copy of each) in the nucleus situated in the head region.

Surrounding the head of the sperm cell is the acrosome cap [shown in blue] - this contains special enzymes that digest the zona pellucida (the membrane surrounding the egg cell) to assist in fertilization.

The mid piece of the sperm cell contains two centrosomes [in green] and coiled mitochondria [gold]. The sperm will contribute both centrosomes to the embryo upon fertilization, which are essential for organising microtubules and thus subsequent cell divisions of the embryo.

The large coiled mitochondria [gold] provide the sperm with the energy supplied to the long flagella (or tail) required for it motility.


In cell biology, the centrosome (Latin centrum ‘center’ + Greek sōma 'body’) is an organelle that serves as the main microtubule organizing center (MTOC) of the animal cell as well as a regulator of cell-cycle progression. It was discovered by Edouard Van Beneden in 1883, and later described and named in 1888 by Theodor Boveri. The centrosome is thought to have evolved only in the metazoan lineage of eukaryotic cells. Fungi and plants lack centrosomes and therefore use other MTOC structures to organize their microtubules. Although the centrosome has a key role in efficient mitosis in animal cells, it is not essential. Centrosomes are composed of two orthogonally arranged centrioles surrounded by an amorphous mass of protein termed the pericentriolar material (PCM). The PCM contains proteins responsible for microtubule nucleation and anchoring including γ-tubulin, pericentrin and ninein. In general, each centriole of the centrosome is based on a nine triplet microtubule assembled in a cartwheel structure, and contains centrin, cenexin and tektin.

[Source: Wikipedia]

Centrosome (borderless version)-en” by Kelvinsong - Own work. Licensed under CC BY 3.0 via Wikimedia Commons.

The Embryo - Cleavage and Genetic Transition

On the left: Image of the mitotic spindle in a human cell showing microtubules in green, chromosomes (DNA) in blue, and kinetochores in red. On the right: Gli1 protein expression labeled in green, DNA labeled red. Gli1 is shown bound to the microtubules during cell division (image courtesy of the Iannaccone Lab, Lurie Children’s Research Center). Nucleus diameters are approximately 10µm, or about four 100,000ths of an inch.

September 13th, 2013

Mom’s genes load proteins and RNAs into the oocyte and control DNA replication in the one-cell zygote as well as the first cleavage which leads to the two-cell stage.  The two-cell stage is where the mouse embryo switches from being controlled by maternal genes to being controlled by the embryo’s genome. In humans this transition happens at the 4-8 cell stage. This changing of the guard is where exclusive expression of genes from Mom prior to fertilization transition to expression of genes from the new embryo. Genes that are now uniquely the product of fertilization.

In other mammals the change in control varies from the 8-cell stage to the 16-cell stage called morulae [pronounced “more-you-lee” and the plural of morula]. Derived from the Latin for mulberries because the morulae are clumps of cells that sort of resemble mulberries.

On the left: Mulberries (adapted from the 1911 Encyclopædia Britannica). On the right: Two rat morulae at the 8-cell stage - morulae are 100 µm in diameter, or about four 10,000ths of an inch (image courtesy of Greg Taborn, Lurie Children’s Research Center).

One example of this shift is RNA polymerase II. The activity of RNA polymerase II has not been found in the one-cell zygote, while it is present in two-cell embryos. [RNA polymerase II is an enzyme (a protein that makes chemical reactions go faster) which is the main machine for turning the genetic code in our DNA into RNA that directs the production of specific proteins (see our previous post Genes, DNA, and RNA)].

Keep reading

19 April 2015

Ready, Steady, Divide!

Cell division allows multicellular organisms to grow, and then to maintain and repair cells and tissues. Now, researchers have identified a mechanism by which parent cells in transparent microscopic worms dictate what sorts of daughter cells are produced. They tracked the process by adding fluorescent tags to key components in a dividing cell (bottom centre in each of the repeated images) – the centrosome (the outer part of the two bright circles) and a protein called beta-catenin (the brighter inner circles). Each oblong blob – seen as purple top left – is DNA. The identity of each daughter cell depends on how much beta-catenin it receives during division and the centrosome appears to regulate that by controlling the amount of time it’s attached to the protein. If the same thing happens in humans the discovery could have clinical relevance because daughter cells receiving too much beta-catenin can divide too quickly and become cancerous.

Written by Daniel Cossins

Image by Bryan Phillips
University of Iowa, USA
Originally published under a Creative Commons Licence
Research published in Current Biology, March 2015