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They discover why we humans have big brains

The human brain has something exceptional. Its relative size compared to the rest of the body is the largest among all species. They have just discovered the genetic key that endows mammals with large brains

A human brain weighs approximately 1,500 g. It is much smaller than that of the elephant, with 5kg of brain, or that of the whale, with 7.8kg. And, of course, there are much smaller ones. The brain of a macaw is the size of a shelled walnut, that of a macaque is the size of a lemon. The brain of a mouse measures just over a centimeter, and weighs the same as a jelly bean.

Now they have just found out what the size of a brain depends on in different species, why mammals have big brains, and other species get by with tiny organs.

Reason is a ‘key’ in the DNA of all species. That key is a small RNA, called MIR3607, which is activated during embryonic development in mammals with very large brains, such as humans, and remains off in those with small brains such as mice.

When the key is activated, the number of neural stem cells increases and thus the formation of neurons increases. These are the conclusions of a study by the group of Neurogenesis and Cortical Expansion led by Víctor Borrell, from the UMH-CSIC Institute of Neurosciences in Alicante.

That this key is activated, that MIR3607 is expressed during the development of the embryo, was selected by evolution, to enhance in most mammals the expansion of the cerebral cortex, the most evolved part of the brain.

The small size of the brain of rodents

In rodents such as mice, the loss of this microRNA led to a small, smooth brain, unlike most mammals, which evolved into large, folded brains.

The number of genes specific and unique to humans is relatively small, while the number of genes conserved and expressed in the cerebral cortex in different mammalian species during embryonic development is much higher. A fundamental question still to be resolved was how the expression of these highly conserved genes that guide the development of the cerebral cortex has been regulated so differently during evolution in different species.

In an article published today in the journal Science Advances , researchers from the Institute of Neurosciences CSIC-UMH, in Alicante, led by Dr. Víctor Borrell, director of the group ” Neurogenesis and cortical expansion ”, has investigated this question by focusing on a gene that gives rise to a microRNA called MIR3607. And they have found that, in species with small brains, such as the mouse, the loss of expression, or “silencing,” of MIR3607 during evolution led to a dramatic decrease in the size of their cerebral cortex, which ultimately determines the size. of the brain. In addition, its cerebral cortex became smooth, compared to that of most mammals, which has increased its surface through convolutions and furrows, as a relief of peaks and valleys.

The genetic mechanisms underlying this secondary loss in the evolution of the rodent brain were completely unknown until now. “With our work we show that the MIR3607 microRNA is expressed embryo in the large cerebral cortex of primates and carnivores, such as the ferret, but not in the mouse.” Víctor Borrell points out.

MicroRNAs (miRNAs) are small RNAs that do not give rise to proteins, but rather regulate the expression of other genes, which is why they are essential during embryonic development. In fact, the evolution of the different animal species goes in parallel with the appearance of new miRNAs that have promoted diversity during embryonic development. However, despite the ability of miRNAs to modulate gene expression, they have surprisingly received little attention in the context of brain evolution and expansion.

“With this work we have identified MIR3607 as an important regulator of the Wnt / β-Catenin signaling cascade, a pathway with key functions in the embryonic development of the cerebral cortex because it regulates processes such as the proliferation of stem cells and cell differentiation. Our findings also fit with recent discoveries about the importance of miRNAs in early cortical development, regulating the amplification of neural stem cells and the homeostasis of the germ layer from which they arise, ”explains Dr. Borrell.

Setback in evolution

From an evolutionary point of view, these results suggest that “the loss of expression of MIR3607 in the development of the cerebral cortex may have been a key factor for the secondary reduction in brain size during the evolution of rodents. The absence of MIR3607 in the embryonic cerebral cortex of the mouse raised the key and still unclear question of how its activation is regulated ”, explains Kaviya Chinnappa, predoctoral researcher and first author of this work.

The general trend in mammalian evolution towards the expansion and folding of the cerebral cortex was reversed in some groups of mammals, such as New World monkeys and especially rodents, and their brains evolved by getting smaller and smooth than those of their ancestors. “Our results identify for the first time that the loss of MIR3607 was selected during the evolution of small mammals, to decrease the size of the cerebral cortex in mice”, Borrell points out.

“MicroRNAs are usually highly conserved among animal species. The similarity of MIR3607 in human, macaque, ferret, and mouse suggests conserved functionality for this microRNA in mouse brain. Therefore, we reasoned that, if we re-express MIR3607 experimentally in the mouse embryonic brain, we could shed light on its role during cortical development, ”explains Chinnappa.

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