Timing Crucial in Brain Development: Study

The outer regions of the brain, the cortex, have specific layers of different cells - neurons - that are similarly ordered among all mammals, from tiny mouse brains to huge elephant brains. However, the proportions of different cell layers vary widely among species, and little is known about how and why this variation happens.

Now, researchers from The University of Osaka have suggested, following intense research on developing brain cells, that these differences are related to the timing of specific signals in the brain during early development. These findings have been published in The EMBO Journal.

The research team began their investigation by focusing specifically on the rat cortex, noting that rats had a much larger deep layer - relative to the upper cortical layer - than seven other mammals, including mice.

Following this initial discovery the brains of rats were compared with those of mice - their closest evolutionary relative - in more detail. The research subsequently reported that this difference was due to the greater numbers of deep layer neurons present, rather than just a larger layer area.

"We next wanted to see how this difference in the number of deep layer neuron arises," says Yuki Yamauchi, lead author of the study. "Using a cell-labeling technique in rats and mice, we saw that rat neural progenitor cells produced more deep layer neurons."

A neural progenitor cell is a type of stem cell that generates neurons while the brain is still developing. To understand why rat brains create more deep layer neurons in early development, the timing of upper and deep layer neuron production in mice and rats was assessed.

Interestingly, mice produced deep layer neurons for one or two days before the progenitor cells switched to producing upper layer neurons, whereas rats produced deep layer neurons for around four days before making this switch.

This difference between rats and mice is likely caused by different timing of the expression of molecules involved in Wnt signaling, a process that is already known to be important for regulating the timing of cortical development. Wnt glycoproteins are key for enacting various cell processes, and rats had prolonged expression of Wnt signaling genes, leading to extended deep layer neuron production.

"As well as highlighting the unusual cortical structure of rats relative to other mammals, we demonstrated that this variation arises from the distinct 'aging rates' of neural progenitor cells," notes senior author of the study Ikuo Suzuki. "This finding broadens our understanding of the different mechanisms underlying divergent brain structure among related species."

These findings from the developing rat cortex will contribute to a deeper understanding of human brain evolution. In turn, this may also help broaden our knowledge of the mechanisms underlying developmental and neurological disorders, with exciting potential applications in regenerative medicine.

Fig. 1

Caption: Title: Species-specific brain evolution driven by the temporal regulation of neuron production

(Top) Evolutionary variation in the thickness of the deep cortical layer across mammalian species. Compared to mice (grey) and other mammals, rats (red) exhibit a notably expanded deep cortical layer.

(Bottom) The developmental mechanism underlying this expansion. During embryonic development, sustained Wnt signaling activity in rats prolongs the production phase of deep-layer neurons, ultimately resulting in a thicker deep cortical layer compared to mice.

Credit: Image reproduced from [Yamauchi et al.], The EMBO Journal ([2026]), under the CC BY 4.0 license.