by Olubusola Olukoya
figures by Corena Loeb

Our ability to take in information from the world around us, make inferences, and execute appropriate reactions is generated by our brains. The brain, which weighs about 1.5 kilograms in the average adult, takes up 20% of our body’s energy expenditure to power a network of roughly 86 billion cells. Ongoing research in the field of neuroscience utilizes various approaches to understand the development and function of brain cells in normal and disease states. After over 200 years of research, we are only just beginning to appreciate how different types of cells are generated in the brain.

There are two major types of cells in the brain: neurons and glia. Neurons are responsible for conducting electrical signals that carry information about brain states and sensations from the external world. Glia, though previously thought to act as a glue connecting neurons, have been shown to play key roles in neuronal development, signaling, maintenance, and repair. Taking a slice through the human brain reveals different organizational structures within the brain that consist of brain cells working together to carry out different functions (Figure 1). One such structure, the cerebral cortex, or cortex for short, has been the subject of many investigations into how different cells are born and organized in the brain. Deep within the brain are fluid-filled spaces called ventricles that secrete cerebrospinal fluid for protecting and maintaining the entire central nervous system.

It all began with the “father” of modern day neuroscience

Santiago Ramon y Cajal is considered the “father” of modern day neuroscience. He was awarded a Nobel prize in 1906 (alongside Camillo Golgi) for work on the structure of the nervous system. Cajal made use of a silver nitrate stain developed by Golgi to visualize cells in the cortex – which were later identified as neurons – and drew exquisite representations of them that continue to be exhibited today. In his drawings, he identified distinct types of neurons based on their different morphologies and  organization in different layers of the cortex. However, the question remained – how do these different cells arise during development?

One cell to give rise to them all

Neurons, like other cells in the body, arise when an ancestor or progenitor cell undergoes cell division. Decades of work in the cerebral cortex have identified that progenitor cells known as radial glia give rise to both neurons and glia. Radial glial cells are a type of neural progenitor cell that begins on the floor of the ventricle, in an area known as the ventricular zone. These cells have processes that then extend upwards towards the inner side of the top of the skull, towards a region called the roof plate. These radial glial cells divide during development to duplicate themselves and generate a “daughter” neuron that uses the radial glial processes to climb towards the top of the cortex (Figure 2). As these daughter cells migrate from their origin place to their final destination, they begin to take on distinct genetic characteristics to become the different types of neurons and glia found throughout the cortex. 

Later in development, radial glial cells detach their process from the roof plate and start to produce glial cells through cell division. This process requires a tight timing control to ensure that the right number of cells are born in the right order. Defects in radial glia cells or in cortical development can lead to disorders like double cortex syndrome, microcephaly, megalencephaly, epilepsy, and hydrocephalus. 

Genes, genes, genes!

While timing is crucial for the proper order of cell division, gene expression also plays an important role. Experiments using mouse genetics have shown that the over- or underexpression of certain genes in radial glial cells can affect cortical layers, daughter cell migration, and the number and types of neurons and glia produced. Radial glial cells are capable of switching their cell fate to produce both neurons and glia. Cell fate refers to the genetic profile that a cell expresses that makes it into a particular type of cell. Scientists are now conducting experiments to uncover how radial glial cells switch from producing neurons to glia, and vice versa, by altering gene expression in animal and cell-culture models. Observations from these experiments have deduced that expression of different genes and the presence of different signaling proteins help to regulate timing control for generating cellular diversity in the brain. Thus early on in development, radial glia express genes that lean towards neuronal cell fate, before switching to a glial cell fate later in development. The molecular logic of this switch is the subject of many studies.

Omics approaches in studying cellular diversity

New technologies are allowing us to discover more diversity in brain cell types than before, and to begin to unlock the molecular logic of how diversity is produced. Previously, information about cell differences was gathered by observing their morphology or position within the brain, but additional information can be found in the genes they express. Ongoing research in the field is applying gene sequencing approaches to uncover even greater heterogeneity in the brain and other parts of the nervous system. In one such technique known as single-cell RNA sequencing (scRNAseq), cells are collected and then given a unique barcode so that the genetic information of each cell can be sequenced and interpreted.

This data can be collected from tissues at different developmental stages to generate a map showing how progenitor cells move over time to become different types of brain cells (Figure 3). This map includes lineage information (what cells come from where), as well as the developmental trajectory i.e. how cell identities arise over time. These methods are now being applied towards understanding the heterogeneity of neurons and glial cells in different brain structures, as well as in the peripheral nervous system, to create a unified picture of cellular diversity in the nervous system. 

Understanding the diversity of cell types in the brain enables us to identify what types of cells are vulnerable to aging and disease, as well as to leverage this diversity to pursue therapeutic avenues for disease. Scientists hope to one day understand how all the cells in the brain are produced, what genes they express, and when they start to express them, so that we can advance the possibilities and efficacy of disease therapeutics.

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Olubusola Olukoya is a fifth year in the PhD program in Neuroscience (PiN) at Harvard. She tweets about her science at @mo_foluwa.

Corena Loeb is a second year in the PhD program in Speech and Hearing Bioscience and Technology.

Cover image by ElisaRiva on pixabay

For More Information:

• To learn more about Ramon y Cajal, read this article.
• For a more in depth look at radial glia, check out this review.
• Read this if you want to learn more about single-cell RNA sequencing.

This article is part of our special edition on diversity. To read more, check out our special edition homepage!