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Where does the fish secrete from: back to the origins of the pituitary gland

Weizmann Institute scientists are challenging a 200-year-old doctrine about the formation of the gland from the secretion of hormones. Their findings may lead to new approaches in the treatment of various medical problems

A surprising observation in the brain of a zebrafish led the scientists of the Weizmann Institute of Science to challenge a 200-year-old doctrine regarding the origin of a small and most vital organ in our brain - the pituitary gland or by its Latin name hypophysis. The research findings, which was conducted in the laboratory of Prof. Gil Lebkowitz, may contribute to a new understanding of the interrelationships between different cells, including hormone-secreting cells, in this gland, and shed new light on diseases in which it is involved.

The pituitary gland of the zebrafish. The variety of cell types are marked in different colors: in purple - phytocytes, in red and green - two types of hormone-producing cells
The pituitary gland of the zebrafish. The variety of cell types are marked in different colors: in purple - phytocytes, in red and green - two types of hormone-producing cells

The pituitary gland is located at the base of the brain, it is the size of a pea in humans, and is a kind of "relay station" of the hormone secretion system from the brain to the body. The gland has been well preserved throughout evolution - and therefore, the one we have shares many characteristics with those of a variety of other animals, both close and distant. The gland consists of two separate lobes, and each one serves different physiological functions: the anterior one releases six main hormones into the bloodstream, including thyroid hormones and growth hormones, while the posterior lobe releases two prominent ones - vasopressin, which regulates the level of salts and fluids in the body, and oxytocin, which regulates reproduction and social behavior . 

The question of the embryonic origin of the pituitary occupied scientists already at the beginning of the 19th century. At the beginning of its development, the embryo consists of three germ layers - the main groups of cells from which all body tissues are formed; The inner layer is called endoderm, the middle mesoderm, and the outer ectoderm. This outer layer, in turn, is divided into two: the oral ectoderm, from which, among other things, the skin, oral cavity, teeth and eyes develop, and the neural ectoderm, from which the brain and parts of the nervous system develop. Until now, the accepted theory was that the cellular origin of the two pituitary lobes is in the ectoderm, with the anterior lobe originating from the cells of the oral ectoderm, while the posterior one is found in the neural ectoderm. This idea was first presented in 1838 by the German embryologist Martin Rathke, and it received support in many studies after that. 

"Our finding contradicted the idea that the two lobes of the pituitary have completely separate origins. There were hints of this in previous studies, but the smoking gun was not shown."

Chiu Chen, a doctoral student in Prof. Lebkowitz's laboratory in the department of molecular biology and the department of molecular neuroscience at the institute, was engaged in genetic mapping of the anterior lobe of the pituitary gland in zebrafish. With the help of imaging methods and modern genetic methods that were not available to researchers in the past, Chen was able to mark different cells in the ectodermal tissue of a zebrafish embryo, and thus follow under a microscope the different cells formed from these cells during the development of the embryo and the formation of the pituitary gland. According to conventional theory, Chen expected to see only cells with genetic markers derived from the oral ectoderm in the frontal lobe. Surprisingly, the origin of some of them was actually in the neural ectoderm.

"This finding contradicted the idea that the two lobes of the pituitary have completely separate origins," says Prof. Levkowitz. "There were indeed hints of this in previous studies, but so far the smoking gun has not been presented that would be conclusive proof of a deviation from the prevailing theory."

The "smoking gun" in the current study is actually cells that were discovered in the apparently wrong lobe. The findings were made possible with the help of a combination of the genetic tracking that Chen used and advanced methods for sequencing the genetic material at the single cell level that were implemented in collaboration with the laboratory of Prof. Ido colleague from the department of systemic immunology at the institute. Using the combination of methods, the scientists were able to decipher the exact molecular composition of the pituitary tissue at the single cell level and track its development in zebrafish embryos.

and meanwhile in London

As the research progressed, the institute's scientists learned that a researcher at the Francis Crick Institute in London, Dr. Karin Rizzotti, encountered a similar finding in mice. "She was skeptical about the findings, but we shared with her that we had reached similar findings in fish and invited her to cooperate and join forces, in order to produce a stronger 'case'," says Prof. Lebkowitz.

Besides breaking the doctrine, the mapping of the central cell types in the pituitary gland led to another surprising finding: dialogue between the two lobes. The researchers discovered that certain cells in the posterior lobe called phytocytes influence the development of hormone-producing cells in the anterior lobe. "We knew that phytocytes are involved in the release of vasopressin and oxytocin from the posterior lobe, now it turns out that they also play a role in the development of the anterior pituitary," says Chen.

"We have a lot of knowledge about the anatomy of the pituitary gland, but when it comes to understanding its molecular composition, there is still a long way to go," says Prof. Levkowitz. "Understanding the genetic differences between the different cells, how these differences are created in the early stages of fetal development, and how the different types of cells affect each other - may help us understand what goes wrong in various diseases in which the pituitary gland is involved, including various types of cancer and certain children's diseases, Like, for example, lack of growth hormone."

Despite the new discoveries, Prof. Lebkowitz points out that the doctrine regarding the separate origins of the two lobes is still largely true, but the current study presents a more complex picture that may lead to new ways of researching disruptions in pituitary activity. Chen explains: "Let's say you have 100 growth hormone cells. 95 of them are indeed found in the oral ectoderm, as was commonly thought. But now it turns out that the origin of five is actually nervous. All these hundred cells release the same hormone - but perhaps they do so in response to different physiological demands? This understanding may open up possibilities for treating diseases resulting from hormonal deficiencies by focusing on specific cells, while avoiding an unwanted effect on other cells."

Dr. Dina Leshkowitz from the Department of Life Science Research Infrastructures of the Institute also participated in the study; Dr. Hanji Lee; Dr. Andreas van Impel; and Prof. Stefan Schulte-Marker of the University of Münster, Münster, Germany.

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