How to create a genius mouse

Scientists find a single gene can create primate-level neural development in the mouse neocortex
August 10, 2015

The left-brain hemisphere of a normal mouse shows the normal level and cellular distribution of the Pax6 gene expression in the developing neocortex. The right-brain hemisphere shows a sustained, primate-like Pax6 expression pattern in the neocortex of a double transgenic mouse embryo. These animals have more Pax6-positive progenitor cells and a higher Pax6 expression level in the germinal layer close to the ventricle in the right hemisphere. (credit: © MPI of Molecular Cell Biology & Genetics)

Researchers at the Max Planck Institute of Molecular Cell Biology and Genetics have created a transgenic mouse in which a gene called Pax6, during embryonic development, is highly expressed in a specific group of brain cortical cells called neural progenitor stem cells (the cells that generate all cells that make up the brain).

The resulting mouse brain generated more neurons than normal and exhibited primate-like features — notably those in the top layer, a characteristic feature of an expanded neocortex.

Mouse basal progenitors, in contrast to human, do not express Pax6. In humans, basal progenitors can undergo multiple rounds of cell division, thereby substantially increasing neuron number and ultimately the size of the neocortex.

“The evolutionary expansion of the neocortex is a hallmark of species with higher cognitive functions,” explains Wieland Huttner, the research group leader and director at the MPI-CBG. “Our findings contribute to our understanding of the molecular mechanisms underlying this expansion. While the findings demonstrate how altering the expression of a single key gene can make a big difference to brain development, a future challenge will be to obtain a comprehensive, integrated view of all the molecular changes that made our brains big.”

The study was published in an open-access paper in the journal PLOS Biology.

The paper, reassuringly, did not mention plans to create a transgenic genius cat in case the transgenic mouse gene escaped the laboratory.

Abstract of Sustained Pax6 Expression Generates Primate-like Basal Radial Glia in Developing Mouse Neocortex

The evolutionary expansion of the neocortex in mammals has been linked to enlargement of the subventricular zone (SVZ) and increased proliferative capacity of basal progenitors (BPs), notably basal radial glia (bRG). The transcription factor Pax6 is known to be highly expressed in primate, but not mouse, BPs. Here, we demonstrate that sustaining Pax6 expression selectively in BP-genic apical radial glia (aRG) and their BP progeny of embryonic mouse neocortex suffices to induce primate-like progenitor behaviour. Specifically, we conditionally expressed Pax6 by in utero electroporation using a novel, Tis21–CreERT2 mouse line. This expression altered aRG cleavage plane orientation to promote bRG generation, increased cell-cycle re-entry of BPs, and ultimately increased upper-layer neuron production. Upper-layer neuron production was also increased in double-transgenic mouse embryos with sustained Pax6 expression in the neurogenic lineage. Strikingly, increased BPs existed not only in the SVZ but also in the intermediate zone of the neocortex of these double-transgenic mouse embryos. In mutant mouse embryos lacking functional Pax6, the proportion of bRG among BPs was reduced. Our data identify specific Pax6 effects in BPs and imply that sustaining this Pax6 function in BPs could be a key aspect of SVZ enlargement and, consequently, the evolutionary expansion of the neocortex.