The ability of humans to think complexly is attributed to a brain region called the ​‘Neocortex,’ which is bigger in humans than in other mammals, such as mice. It is responsible for higher-order functions such as thinking, decision-making, memory, consciousness, and language. Although the Neocortex originates from similar type of stem cells in both humans and mice, it is bigger in humans, puzzling researchers. To understand this mystery, researchers led by Bhavana Muralidharan, Principal Investigator at the Institute for Stem Cell Science and Regenerative Medicine (InStem), Bangalore, delved into the development of the human brain in the womb.

During embryo development, specialised Neural stem cells give rise to billions of neurons and glial cells in the brain. These cells can divide and copy themselves, or alternatively, differentiate into other cell types such as neurons. The delicate balance between Neural stem cell division and differentiation during embryo development is crucial for generating the correct brain size.

The fate of stem cells is governed by the packaging of DNA, wherein certain genes become more accessible and active than others. The DNA double helix is tightly wound around proteins called ​‘Histones’. Proteins like Lysine specific histone demethylase (LSD1)can chemically modify Histones, thereby altering how tightly or loosely the DNA is coiled around histones. By making certain genes accessible, histone-modifying proteins like LSD1 impact stem cell fate.

To understand the role of the histone modifier LSD1 in brain development, researchers analysed the genes controlled by LSD1. They cultured neural stem cells in the lab using special media and care. Muralidharan states, 

Optimising the growth conditions for growing human neural stem cells and their differentiation consumed a significant portion of our time. Having acquired the capability now, we have shared this knowledge through workshops, providing hands-on training.

The researchers discovered that LSD1 decreases the activation of genes that control how cells stick to each other (Cell adhesion genes) and the interaction with their environment (Extracellular Matrix genes). Interestingly, these genes are more active in human neural stem cells compared to mouse neural stem cells in the human cortex.

Yogita Adlakha, Associate Professor, Amity University Noida quotes,

It is commendable that the authors have examined both DNA binding and RNA levels to understand the genes activated by LSD1 and have compared their data with published datasets.

However certain findings of the study could have been validated through 3D based cerebral organoid models which are tiny self-organised 3‑dimensional tissue structures that resemble different regions of the brain, she suggests.

Although LSD1 is present in a wide range of organisms, it specifically targets human genes that promote neural stem cell identity. By controlling these human-specific target genes in neural stem cells, LSD1 exhibits intriguing functions unique to the developing human brain. Muralidharan expresses optimism, stating, ​“With our work we are able to decipher ways by which the human neuron generation is different from its mouse counterpart. This also would be interesting in the context of neurodevelopment disorders because mutations in LSD1 lead to a form of cognitive impairment. Studies of this nature are also important to understand many neurodevelopment disorders like autism.” 

Muralidharan adds that the same model system will soon be used by their lab to understand how perturbations in LSD1 function may underlie cognitive impairment. These findings can not only shed more light on the evolution of intelligence in humans but also help in the development of more effective treatment for neurodevelopment disorders like autism.