The origin of the mammalian brain uncovered

June 28th, 2018

The mammalian brain is characterised by the development of a vast neocortex that is superposed to the ancien ‘reptilian’ paleocortex. This distinction derives from how neurones are made: by direct neurogenesis in the paleocortex, and by indirect neurogenesis in the neocortex. But how different parts of the brain decide which developmental mechanism to use? A team of researchers lead by Victor Borrell at the Neuroscience Institute in Alicante (Spain) in collaboration with American and German researchers, as well as Athanasia Tzika in the Department of Genetics and Evolution of the University of Geneva and the SIB Swiss Institute of Bioinformatics, has discovered that the control of the direct versus indirect neurogenesis depends only on the expression of three genes. To test their hypothesis, the scientists have inverted the process: generating mammalian cortical tissues in the snake and reptilian tissue in the mouse ! These results, published today in the journal Cell, open a new era in our understanding of the development and evolution of the brain. 

In mammals, including humans, the making of neurones from Radial Glia Cells (RGCs) happens either by ‘direct neurogenesis’ forming the so-called ‘reptilian’ paleocortex (controlling the sens of smell, body temperature and other vital fonctions), or by ‘indirect neurogenesis’ forming the neocortex (controlling higher-order brain functions such as spatial reasoning or langage). During direct neurogenesis, each RGC produces one neurone. This process is fast but produces only a limited number of neurones. Conversely, during indirect neurogenesis, RGCs are amplified by cell division and by their differentiation into Intermediate Progenitor Cells (IPCs) that generate neurones. This process is slower but produces a very large number of neurones that populate the mammalian neocortex. But how can RGCs choose to undergo direct or indirect neurogenesis?

Three genes to explain the development and evolution of the brain 

To answer this question, Victor Borrell and his colleagues teamed up with Athanasia Tzika from the Department of Genetics and Evolution at the University of Geneva (UNIGE) and the SIB Swiss Institute of Bioinformatics, a specialist of reptilian animal models. The initial idea was to compare the snake brain with the ‘reptilian’ paleocortex of the mouse in order to examine if the same genes are expressed in the corresponding neural tissues. “We have observed that two genes, Robo1 and Robo2, are highly expressed during direct neurogenesis, while the gene Dll1 is very little expressed, both in snakes and in the paleocortex of the mouse” says Athanasia Tzika. “During indirect neurogenesis in the neocortex of the mouse, we observed the inverse situation: Robo1 and 2 are very little expressed and Dll1 is strongly expressed”. This first important result suggests that these three genes control the neurogenetic choice made by RGCs. This hypothesis is very surprising because scientists considered until now that the evolution of the neocortex in mammals required the advent of multiple new genes. 

Building a mammalian brain on command ? 

If the making of reptilian versus mammalian cortex only depends on the expression of these three genes, it should be possible to control the type of neurogenesis by artificially controlling these genes! Using molecular biology techniques, the team of researchers  increased the expression of Robo1 and 2 and reduced the expression of Dll1 in the neocortex of the mouse, and indeed observed that RGC started to produce neurones by direct neurogenesis as in a reptile. Even more surprising, the reverse experiment on a snake embryo caused indirect neurogenesis: neo-cortical tissue was produced as in a mammalian brain! “The fact of triggering indirect neurogenesis in a reptile brain proves that this process is very old and that mammals have acquired the ability to modify it by controlling the expressions of only three genes” indicates Athanasia Tzika. 

A small change for spectacular consequences 

Some defects in brain development are caused by abnormal neurogenesis. This discovery of the mechanisms at the core of the development and evolution of the mammalian neocortex might therefore allow for a better understanding of these cerebral defects, including in human.

For additional informations, download the original article here:  

Evolution of Cortical Neurogenesis in Amniotes Controlled by Robo Signaling Levels.
Cardenas et al., 2018, Cell 174, 1–17