Brain chemical serotonin involved in early embryo patterning

Discovery provides keys to evolution of neuronal signalling, ’left-right asymmetry’

Boston–Forsyth Institute researchers have found that serotonin-the chemical substance involved in transmitting signals between neurons and which plays a role in anxiety and mood disorders– is present in vertebrate embryos long before neurons form. The scientists also found that serotonin plays a key role in determining where organs are positioned in the body during embryonic development.

The study, published in the May 10 Current Biology, has ramifications for neuroscience, developmental genetics, evolutionary biology and, possibly, human teratology (a branch of pathology and embryology concerned with abnormal development and congenital malformations).

Among other results, the study, which was carried out on frog and chick embryos:

• Provides the first molecular support for the idea that serotonin is utilized as a large-scale left-right patterning mechanism, thus offering new insight into the basis of position of the heart and other asymmetric, visceral organs.
• Identifies a possible novel serotonin signaling pathway, providing evidence that serotonin can signal inside the cell. If also found in mammals, such signaling, which may be important in brain functioning, would suggest numerous new roles and possible targets for serotonin-related drugs like the selective serotonin reuptake inhibitors (SSRI antidepressants such as Prozac and Zoloft) or the monoamine oxidase inhibitors (MAOIs).
• Could lead to a greater understanding of potential health risks from drug families that target the serotonin pathway in human patients.
• Sheds light on the evolutionary origin of a crucial neurological control system, suggesting that neuronal synapses using serotonin as a neurotransmitter may have arisen through the adaptation of ancient, fundamental cell-cell signals to a new purpose as nervous systems evolved.

The team was led by principal investigator Michael Levin, PhD, Associate Member of the Staff, whose laboratory focuses on understanding the role played by flows of ions and other small molecules in determining body patterning during embryonic development and regeneration. According to Levin, “We hope that through better understanding of important but previously little-studied biophysical signals, new therapeutic applications can be developed.”

One important goal is to find ways to prevent or treat laterality-related birth defects such as isomerism (a loss of asymmetry such as when a body has a midline heart or two spleens), heterotaxia (in which various organs are randomly located on the correct or incorrect sides of the body), or situs inversus (in which all organs are located on the opposite side of the body).” Such defects affect about one in 8 thousand babies born to term.

The Study

In the current study, the researchers found that frog embryos contain a supply of serotonin provided in the egg by the mother. This maternal supply of serotonin functions during the first few cell divisions and then is degraded by an enzyme (Monoamine Oxidase) which has many important functions in human neuro-medicine. Chick embryos, on the other hand, synthesize their own serotonin shortly after laying. Though details (such as the origin of the serotonin) differ, both species utilize serotonin signaling as a patterning mechanism long before the appearance of the nervous system– suggesting that this novel role for serotonergic signaling may be conserved in a number of different species.

SIGNIFICANCE

Evolutionary Biology

Regarding the study’s evolutionary significance, Levin said: “This work demonstrates that a signaling mechanism previously believed to exist only in neuronal synapses is, in fact, also a signal used by communicating primitive embryonic cells–thus illustrating a fascinating re-use of cellular control systems in evolution. The mechanism can now be studied in a wide selection of organisms as scientists work to understand the most common and fundamental mechanisms guiding pattern formation across phyla.”

Clinical

Jean M. Lauder, Ph.D., Professor of Cell and Developmental Biology at the University of North Carolina School of Medicine at Chapel Hill said: ” Dr. Levin’s team presents exciting new evidence that serotonin, a brain chemical or “neurotransmitter” that is involved in mood disorders and depression and is targeted by antidepressants like Prozac, plays critical roles in early embryonic (prenatal) development of left-right asymmetry of body organs like the heart, gall bladder, and gut.

“This is the first time that a “neurotransmitter” has ever been shown to be a critical patterning signal during development of the vertebrate body plan. This study provides evidence that early embryonic cells have ways of sensing serotonin other than by the synaptic mechanisms that have previously been described in the nervous system.

“Although neurotransmitters like serotonin are known to regulate development of cells and tissues outside the nervous system, no study has ever before shown that they could regulate such things as the shape, laterality, or placement of tissues or organs in the body.

“The possible clinical significance is that serotonergic drugs, if taken by the pregnant woman, might disrupt normal development of the body plan in the fetus. This study also opens up new possibilities for drug discovery to find therapies to prevent malformations caused by errors in these important aspects of prenatal serotonergic signaling.”

Embryonic Asymmetry

In the words of Professor Dr. Martin Blum of the University of Hohenheim Institute of Zoology: “Dr. Levin’s fascinating new data add to the mounting evidence for a cilia-independent mechanism of symmetry breakage in the frog which acts very early, during the first few cell divisions. It will be extremely exciting to find out how serotonin signaling connects to the left-asymmetric signaling cascade, and if and how such a mechanism is conserved in other vertebrates, particularly the mouse.”

Medical, Neurological

Lewis Wolpert, FRS Emeritus Professor of Biology as Applied to Medicine, Anatomy, and Developmental Biology at the University College, London said: The study is “very impressive and totally unsuspected. This is a rare truly novel finding opening up a new world in development of asymmetry and perhaps more. Who would have thought that depression might be related to handedness?”