“Section through the cerebral cortex of a mouse, stem cells can be seen glowing in green, mature nerve cells in red; cell nuclei for both types of cell are shown in blue.” Source: IMBA

Your brain is a complex, highly organized organ. Each mammalian brain is made of approximately 10-15 billion nerve cells, called neurons. And each brain is built of thousands of different types of neurons, called neuronal subtypes. Neurons have the amazing ability to gather and transmit electrochemical signals, the more neurons the faster signals can be transmitted; think of them like the gates and wires in a computer. It has been known that neurons arise from a small set of progenitor cells that divide in a spatially and temporally controlled manner to generate a fully functional adult cortex.  However what drives daughter cells of these progenitors to different fates is poorly understood.

So the more nerve cells a brain is able to make, the smarter an organism should be. Turns out that humans are really good at it! Stem cells in the human brain produce far more nerve cells than corresponding cells in mice. Jürgen Knoblich and his research team at the Vienna Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) found out what mechanisms are responsible, and why the orientation of the cells plays a role.

It is understood that although the genes of mice and humans are more than a 90% alike, the cerebral cortex of a mouse has around eight million neurons while in humans there are more than 10-15 billion. Nerve cells are produced in the brain of the embryo from stem cells that continuously divide. Each dividing stem cell gives rise to a nerve cell and another stem cell.  So how could it be that humans have more neurons – and a much larger brain – than mice? The Knoblich laboratory suggests that it has to do with controlling the direction of cell division.

Generally spoken each stem cell can divide in different spatial planes (or directions); the daughter cells are then either ‘up and down’ or ‘left and right.’ According to current understanding the direction of division of stem cells defines whether new nerve cells, or only new stem cells, are produced. This is called a positional effect.

The IMBA scientists bred mice in which the direction of division of the stem cells can be controlled. This regulation is possible by using the protein ‘Inscuteable,’ which works like a switch for the direction of division: cells divide horizontally with Inscuteable but vertically without the protein.

Studies of the mice with Inscuteable showed that nerve cells are actually generated in both vertical and horizontal divisions (and not only in one); however the cells were far more parallel to the cell surface. So a mouse with more Inscuteable protein has more horizontal divisions, and so overall more nerve cells. A lack of Inscuteable has the opposite effect. This mechanism could be responsible for the tremendous proliferation of nerve cells in the human brain!

But how does a human brain manage to generate the correct numbers of neurons?

Higher organisms like humans reproduce nerve cells through a ‘detour,’ meaning horizontal division initially creating a stem cell and an intermediate progenitor. This cell has lost its stem cell properties but can still divide, on average once in mice, so that two nerve cells are generated per horizontal stem cell division. This indirect neurogenesis is also controlled by the Inscuteable protein.

Indirect neurogenesis seems to be the key to larger and more intelligent brains. If we compare mice to organisms with less developed brains we can see that they are lacking this kind of fast neurogenesis and have accordingly fewer nerve cells. Therefore indirect neurogenesis is a very important in terms of evolution. In humans intermediate progenitors are already much more complex and divide more frequently than in the mouse; therefore compared with mice, humans have a plethora of nerve cells.

The researchers also tried to determine  whether the mice without the Inscuteable protein are dumber than their counterparts due to fewer nerve cells, or whether an artificially induced overproduction of the protein could lead to more intelligent animals, but couldn’t prove either hypothesis, yet.

So does the Inscuteable protein make man human? “Far more interesting however is the role played by Inscuteable in humans” says Jürgen Knoblich. “It probably also regulates the number of neurons in our own bodies by activating indirect neurogenesis, the evolution of the protein and its function may have contributed to the enormous enlargement of the human brain.”

This hypothesis is supported by the finding that the division pattern of the intermediate progenitors closely correlates with the level of intelligence. This specific pattern only appears in primates, including humans, so without Inscuteable we would certainly not be what we are.

References:

Mouse Inscuteable Induces Apical-Basal Spindle Orientation to Facilitate Intermediate Progenitor Generation in the Developing Neocortex  Maria Pia Postiglione, Christoph Jüschke, Yunli Xie, Gerald A. Haas, Christoforos Charalambous, Juergen A. Knoblich Neuron – 20 October 2011 (Vol. 72, Issue 2, pp. 269-284)

Cholesterol is a crucial fat-like substance produced by the liver that is required for bodily functions. It is the main sterol synthesized and transported in the blood plasma of all animals. Cholesterol is responsible for a number of functions such as:

1. Building and maintenance of the cell membranes
2. Production of sex hormones (androgens and estrogens)
3. Production of bile
4. Metabolism of fat-soluble vitamins, including vitamins A, D, E, and K
5. Insulation of nerve fibers
6. Conversion of sunshine into vitamin D

Cholesterol being a crucial part of our development can have a dark side. The gene DHCR7 (7-dehydrocholesterol reductase) found on chromosome 11 is responsible for the production of cholesterol and mutations in the gene may lead to a metabolic disorder known as SLOS (Smith-Lemli-Opitz Syndrome). This disorder currently occurs once out of every 20,000 births. Individuals with SLOS are unable to produce enough cholesterol to support normal growth and development. This leads to developmental delays, physical malformations, mental retardation and issues with major organs such as the heart. Currently the only treatment for the disorder is cholesterol supplementation to improve growth and developmental progress.

SLOS is inherited in an autosomal recessive pattern, basically both copies of the gene within a cell are mutated. This identifies that the parents of a person with SLOS each carry a mutated copy of the gene, however they do not have any symptoms or signs of SLOS. It may be that genetic counseling may be one form of a preventative method for the disorder. This brings up a great question, should genetic counseling be mandatory for potential parents to decrease transmission of severe genetic disorders?

The neurons fire pulses with periods of rest in between. This is commonly seen in sleeping adults. These pulses were seen between neurons located in the cerebral cortex. The cerebral cortex is involved in sensory information, thinking, emotion and consciousness. Even when they are not receiving input, the neurons will continue the pattern of firing and resting. When we sleep, our neurons will fire and rest as a way of reminding the rest of the brain that even though those cells are no longer working, they’re still alive! It’s as if the neurons are reminding the rest of the brain that they’re still there. Because this is seen in adults and in fetuses, this suggests that this alternative firing and resting activity is a very basic feature of the brain that starts occurring in very early developmental stages.

But now why are they firing so early in life? A mouse’s neurons will fire in synchronized waves. This plays a role in wiring the nervous system during development in order to link the neurons to corresponding body parts. Could this be the same for the human brain? Researchers are unsure if the developing neurons in lab dishes are in synch. If they are, the firing could be part of a mapping process during development.

Using this research, researchers might be able to soon look into what the result is when these neurons don’t form in the right places. The wrong positions might result in numerous disorders. Autism Spectrum disorders may also be related to improper firing.