Lifeboat Foundation

When the right gene is expressed in the right manner in the right population of stem cells, the developing mouse brain can exhibit primate-like features. In a paper publishing August 7th in the Open Access journal PLOS Biology, researchers at the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) succeeded in mimicking the sustained expression of the transcription factor Pax6 as seen in the developing human brain, in mouse cortical progenitor cells. This altered the behavior of these cells to one that is akin to that of progenitors in the developing primate neocortex. Consequently, the mouse progenitors generated more neurons — a prerequisite for a bigger brain.

The neocortex consists of different types of progenitors, but one particular class, the basal progenitors, behave differently in small-brained animals such as mice than in large-brained animals such as humans. In humans, basal progenitors can undergo multiple rounds of cell division, thereby substantially increasing neuron number and ultimately the size of the neocortex. In mice, these progenitors typically undergo only one round of cell division, thus limiting the number of neurons produced. A potential cause underlying this difference in the proliferative capacity of basal progenitors could be the differential expression of Pax6 between species. Mouse basal progenitors, in contrast to human, do not express Pax6. “We were very curious to see what would happen if we were to change the expression pattern of Pax6 in developing mouse brain to mimic that observed in large-brained animals”, says Fong Kuan Wong, a PhD student in the lab of Wieland Huttner and first author of the study.

To this end, another PhD student in the lab, Ji-Feng Fei, generated a novel transgenic mouse line. This line provided the basis for altering the expression of Pax6 in the cortical stem cell lineage such that it would be sustained in basal progenitors. The researchers then introduced the Pax6 gene into the stem cells of these mice. Strikingly, sustaining Pax6 expression in mouse basal progenitors increased their capacity to undergo multiple rounds of cell division, as typically observed in primates. This not only expanded the size of the basal progenitor population in a way somewhat reminiscent to what is seen in large-brained animals. It also resulted in an increase in cortical neurons, notably those in the top layer, another characteristic feature of an expanded neocortex.

About 99 percent of human genes are shared with chimpanzees. Only the small remainder sets us apart. However, we have one important difference: The brain of humans is three times as big as the chimpanzee brain.

During evolution our genome must have changed in order to trigger such brain growth. Wieland Huttner, Director and Research Group Leader a the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG), and his team identified for the first time a gene that is only present in humans and contributes to the reproduction of basal brain stem cells, triggering a folding of the neocortex. The researchers isolated different subpopulations of human brain stem cells and precisely identified, which genes are active in which cell type. In doing so, they noticed the gene ARHGAP11B: it is only found in humans and in our closest relatives, the Neanderthals and Denisova-Humans, but not in chimpanzees. This gene manages to trigger brain stem cells to form a bigger pool of stem cells. In that way, during brain development more neurons can arise and the cerebrum can expand. The cerebrum is responsible for cognitive functions like speaking and thinking.

Wieland Huttner’s researchers developed a method that isolates and identifies special subpopulations of brain stem cells from the developing human cerebrum. No one has managed to do this so far. The scientists first isolated different stem and progenitor cell types from fetal mice and human cerebrum tissue. In contrast to the big and folded human brain, the brain of mice is small and smooth. After the isolation, the researchers compared the genes that are active in the various cell types and were able to identify 56 genes that are only present in humans and which play a role in brain development. “We noticed that the gene ARHGAP11B is especially active in basal brain stem cells. These cells are really important for the expansion of the neocortex during evolution,” says Marta Florio, PhD student in Wieland Huttner’s lab, who carried out the main part of the study.

The neocortex is the part of the brain that enables us to speak, dream, or think. The underlying mechanism that led to the expansion of this brain region during evolution, however, is not yet understood. A research team headed by Wieland Huttner, director at the Max Planck Institute of Molecular Cell Biology and Genetics, now reports an important finding that paves the way for further research on brain evolution: The researchers analyzed the gyrencephaly index, indicating the degree of cortical folding, of 100 mammalian brains and identified a threshold value that separates mammalian species into two distinct groups: Those above the threshold have highly folded brains, whereas those below it have only slightly folded or unfolded brains. The research team also found that differences in cortical folding did not evolve linearly across species.

The Dresden researchers examined brain sections from more than 100 different mammalian species with regard to the gyrencephaly index, which indicates the degree of folding of the neocortex. The data indicate that a highly folded neocortex is ancestral – the first mammals that appeared more than 200 million years ago had folded brains. Like brain size, the folding of the brain, too, has increased and decreased along the various mammalian lineages. Life-history traits seem to influence this: For instance, mammals with slightly folded or unfolded brains live in rather small social groups in narrow habitats, whereas those with highly folded brains form rather large social groups spreading across wide habitats.

A threshold value of the folding index at 1.5 separates mammalian species into two distinct groups: Dolphins and foxes, for example, are above this threshold value – their brains are highly folded and consist of several billion neurons. This is so because basal progenitors capable of symmetric proliferative divisions are present in the neurogenic program of these animals. In contrast, basal progenitors in mice and manatees lack this proliferative capacity and thus produce less neurons and less folded or unfolded brains.

During fetal development of the mammalian brain, the cerebral cortex undergoes a marked expansion in surface area in some species, which is accommodated by folding of the tissue in species with most expanded neuron numbers and surface area. Researchers have now identified a key regulator of this crucial process.

Different regions of the mammalian brain are devoted to the performance of specific tasks. This in turn imposes particular demands on their development and structural organization. In the vertebrate forebrain, for instance, the cerebral cortex – which is responsible for cognitive functions – is remarkably expanded and extensively folded exclusively in mammalian species. The greater the degree of folding and the more furrows present, the larger is the surface area available for reception and processing of neural information. In humans, the exterior of the developing brain remains smooth until about the sixth month of gestation. Only then do superficial folds begin to appear and ultimately dominate the entire brain in humans. Conversely mice, for example, have a much smaller and smooth cerebral cortex.

“The mechanisms that control the expansion and folding of the brain during fetal development have so far been mysterious,” says Professor Magdalena Götz, a professor at the Institute of Physiology at LMU and Director of the Institute for Stem Cell Research at the Helmholtz Center Munich. Götz and her team have now pinpointed a major player involved in the molecular process that drives cortical expansion in the mouse. They were able to show that a novel nuclear protein called Trnp1 triggers the enormous increase in the numbers of nerve cells which forces the cortex to undergo a complex series of folds. Indeed, although the normal mouse brain has a smooth appearance, dynamic regulation of Trnp1 results in activating all necessary processes for the formation of a much enlarged and folded cerebral cortex.

As outlined in a study published in Developmental Cell, researchers have discovered a novel function for p27 in the control of interneuron migration in the developing cerebral cortex.

The cerebral cortex is one of the most intricate regions of the brain whose formation requires the migration and integration of two classes of neurons: the projection neurons and the interneurons. These neurons are born in different places and use distinct migration modes to reach the cortex. While several signaling pathways involving various molecules have already been associated with projection neuron migration, the molecular mechanisms that control interneurons migration remain elusive.

In this study, researchers unveiled a novel activity of p27—a protein initially described for its activity as cell cycle regulator—in dynamic remodelling of the cell skeleton. This skeleton, named cytoskeleton, underlies tangential migration of interneurons in the cerebral cortex. Juliette Godin, primary researcher states: At the molecular level, p27 acts on two cytoskeletal components, the actin and the microtubules. It promotes nucleokinesis and branching of the growth cone through regulation of actine. In addition, it promotes microtubule polymerisation in extending neurites. Both activities are required for proper tangential migration of interneurons in the cortex.

The cerebral cortex, which controls higher processes such as perception, thought and cognition, is the most complex structure in the mammalian central nervous system. Although much is known about the intricate structure of this brain region, the processes governing its formation remain uncertain. Research led by Carina Hanashima from the RIKEN Center for Developmental Biology has now uncovered how feedback between cells, as well as molecular factors, helps shape cortical development during mouse embryogenesis.

The cortex is made up of layers of interconnecting cells that are produced in a particular order from progenitor cells. The relatively cell-sparse outer layer is formed first, then the dense deep layer, and finally the tightly packed upper layer. Hanashima and her colleagues were interested to discover exactly how the various layers form, so they created a mouse model that enabled them to control the expression of a particular protein, Foxg1, known to be involved in cortical development.

The Foxg1 gene, if switched on toward the end of embryogenesis after the outer layer of neurons has formed, triggers the production of deep-layer neurons, followed by upper-layer neurons (Fig. 1). The researchers found that it does this by repressing the activity of another gene, called Tbr1, in the outer-layer neurons.

Say you live across from a bakery. Sometimes you are hungry and therefore tempted when odors waft through your window, but other times satiety makes you indifferent. Sometimes popping over for a popover seems trouble-free but sometimes your spiteful ex is there. Your brain balances many influences in determining what you’ll do. A new MIT study details an example of this working in a much simpler animal, highlighting a potentially fundamental principle of how nervous systems integrate multiple factors to guide food-seeking behavior.

All animals share the challenge of weighing diverse sensory cues and internal states when formulating behaviors, but scientists know little about how this actually occurs. To gain deep insight, the research team based at The Picower Institute for Learning and Memory turned to the C. elegans worm, whose well-defined behavioral states and 302-cell nervous system make the complex problem at least tractable. They emerged with a case study of how in a crucial olfactory neuron called AWA, many sources of state and sensory information converge to independently throttle the expression of a key smell receptor. The integration of their influence on that receptor’s abundance then determines how AWA guides roaming around for food.

“In this study, we dissected the mechanisms that control the levels of a single olfactory receptor in a single olfactory neuron, based on the ongoing state and stimuli the animal experiences,” said senior author Steven Flavell, Lister Brothers Associate Professor in MIT’s Department of Brain and Cognitive Sciences. “Understanding how the integration happens in one cell will point the way for how it may happen in general, in other worm neurons and in other animals.”

Summary: The TOB gene plays a significant role in reducing depression, anxiety, and fear in mouse models. The findings could have positive implications for developing new treatments for disorders associated with psychiatric stress.

Source: OIST

First characterized in Prof. Tadashi Yamamoto’s former lab in Japan in 1996, the gene Tob is well known for the role it plays in cancer. Previous research has also indicated that it has a hand in regulating the cell cycle and the body’s immune response.

The activity of neurons has been measured in a slice of mouse tissue using a quantum diamond sensor – and it might one day enable a new type of non-invasive brain scanning.