Introduction

The Chun lab’s research covers a broad array of seemingly diverse topics. All of our projects were born from a long-standing interest in understanding how the brain develops. Brain development is an incredibly complex process involving the birth, death, migration, and connection of literally billions of cells. Uncovering how each of these steps is regulated will help us discover what goes wrong in developmental brain disorders, as well as how developmental processes affect adult brain function and dysfunction.

Our research is divided into two main scientific pursuits: the first area focuses on understanding the biological functions of certain fat derivatives, called lysophospholipids; the second area studies a type of genetic diversity in the brain, aneuploidy.

Lysophospholipids (LPs)

There has been much media discussion on the importance of “good fats” in the diet, such as omega-3 fatty acids. The fat you ingest is largely in the form of triglycerides, made up of 3 fatty acids, which are absorbed by your body and broken down into free fatty acids. These free fatty acids are used to build the
phospholipids that make up the cell membrane of every cell in the body.Some phospholipids can be further metabolized into lysophospholipids with one fatty acid chain. The breakdown and formation of all these lipid molecules is a dynamic process that is constantly altering the cellular environment in response to external stimuli.

Why are these tiny fat molecules so interesting? It turns out lysophospholipids are important for communication between cells. They can tell cells to divide or move; they can prevent cells from dying; and in some cases, they instruct cells as to which cell type to become. On a larger scale, they are important for reproduction, heart function, immunity, and brain development.

Our research on LPs began when we discovered the first lysophospholipid receptor, called LPA1. LPA1 is expressed in the brain specifically during the period of development when neurons are born, and is activated by the lysophospholipid, lysophosphatidic acid (LPA).

To understand how LPA affects brain development, we developed a method for studying the mouse brain in culture.  After carefully dissecting a mouse embryo, we can incubate its brain in a special media that is similar to the womb environment where it will continue to grow for up to 24 hours. When half of the brain is incubated in media with LPA and the other half without LPA, we see dramatic differences.  In just 18 hours, LPA can cause the mouse brain to grow thicker, generate more neurons, and fold in on itself, much like the folds of human brains. 

We are now investigating how LPA communicates with the brain to produce these effects.  This research may be relevant for several types of human childhood brain disorders, such as polymicrogyria (too many brain folds), lissencephaly (smooth brain), and microcephaly (small brain).

Another way to determine how LPA is involved in brain development is to study what happens when you take away the receptor it uses to communicate.  We have created genetic mutant mice which no longer have the gene for LPA1. Mice missing the LPA1 gene do not seem to develop much differently from their normal counterparts. However, we now know that there are, in fact, 5 receptors that are activated by LPA, so when one is missing, others may take over for it. In addition, another lysophospholipid, called sphingosine 1-phosphate (S1P), looks and acts similar to LPA. We have created mice missing several of the receptors activated by S1P as well. By studying the behavior and anatomy of mice missing each receptor and cross breeding them to generate mice missing multiple receptors, we hope to learn more about the biology of these lipids.  

So far, we have made several important findings using these mutant mice.

Reproduction: Mice missing the LPA3 gene have fertility problems. Normal female mice have litters of 8-12 pups, which each develop with their own placenta in the uterus. Without the gene for LPA3, embryos are not evenly spaced inside the uterus, causing embryos to share placentas and often die. We hope that studying these mice will reveal important clues about the development of human babies in pregnant women with multiple fetuses.

Male mice that do not have LPA3 have low sperm counts resulting in poor fertility. We are studying how LPA keeps sperm healthy, with the aim towards therapies to improve fertility in men with low sperm counts.  

Hearing: The relationship between lysophospholipids and hearing was discovered serendipitously when we noticed mice missing the S1P2 and S1P3 receptors tilt their head at an awkward angle and cannot tell which way is “up” in certain behavioral tests.
This inability to sense gravity is related to inner ear problems, similar to vertigo in humans. When we tested their ability to hear, we found out that almost all mice without S1P2 and
S1P3 are deaf. The mice, however, are normal at birth, but progressively lose the ability to hear and sense gravity over the first weeks of life. We are now testing whether drugs that affect S1P can protect mice from hearing loss.

Multiple Sclerosis: MS is a disease in which the body’s immune system attacks the nerves, producing gradual and permanent paralysis. There is currently a drug being tested in clinical trials on humans with MS, called FTY720, that seems to help slow the progression of the disease. The way FTY720 works is not completely understood, although it is known to activate several S1P receptors. We have developed a mouse model of MS which responds to FTY720 similar to humans (i.e. the paralysis can be stopped with drug treatment). By studying how the drug works in mice, we hope to get a better idea of how it works in humans with MS, which will help us predict how people will respond to treatment.

Aneuploidy

The human brain contains an enormous diversity of cells all born from a relatively small number of neural stem cells. Our lab has been interested in understanding how such complexity is generated in the brain.
	Cells in the developing brain divide very rapidly.  During a normal cell division, DNA is replicated then distributed equally into each daughter cell. In order for the cell to track the distribution of DNA, it is packaged into chromosomes. Human cells have 23 pairs of chromosomes (46 chromosomes total), one copy contains the mother’s genes and the other contains the father’s genes. Each chromosome contains hundreds of genes that encode for all the components that make up cells, tissues, and organs of the body.
We observed that sometimes the chromosomes are not equally distributed when cells in the developing brain divide. This results in cells with less than or more than two copies of each chromosome; we call these aneuploid cells.

Aneuploid cells are found outside of the brain, most notably in cancer cells. Textbooks continue to teach the idea that every cell must have 23 pairs of chromosomes – no more, no less – in order to function normally. Cells that have lost or gained chromosomes are presumed to either die or become cancerous. However, our research is beginning to amend this notion. We have found that aneuploid cells are produced in high numbers in the developing brain, and although many of these cells do die, many of them also survive to become part of the adult brain.

This research is cutting-edge, so there are still many unknowns. We don’t yet know how many of the cells in a normal human brain are aneuploid, though we estimate it could be as high as one in four!  Another outstanding question is why these aneuploid cells exist, specifically in the brain. When we look at white blood cells, over 99% of them have 46 chromosomes. We speculate that aneuploidy contributes to the diversity of cells, allowing the brain to perform highly complex functions such as learning, memory, and creative thought.