A monoamine neurotransmitter regulates stem cells: : A lesson from the fruit fly Drosophila melanogaster


Stem cells are undifferentiated long-lived cells characterized by two important features. They have an intrinsic self-renewing capacity, by which they divide asymmetrically and symmetrically to perpetuate the stem cell pool throughout life. Also, they can give rise to several mature cell lineages under appropriate conditions, a property known as multilineage potential or differentiation potency. Unhealthy stem cells can affect tissue integrity with deleterious effects that can lead to diseases. Studies have shown that a large number of stem cells reside in a specialized niche or microenvironment where they get exposed to local signals needed for their identity and function. In recent studies, researchers have revealed that signals outside the tissue such as neurotransmitters and hormones regulate stem cell activity. Researchers have found the ovaries of the fruit fly Drosophila melanogaster to be an excellent model system on how both local niche signals and signals outside the tissue shape stem cell lineages. Current studies on the germline stem cell of D. melanogaster have provided more information on how signals in the external environment influence the systemic regulation and maintenance of stem cell proliferation. One of the recent studies have found that mating with males induces female germline stem cell proliferation in D. melanogaster. For mating-induced germline stem cell proliferation, the male seminal fluid protein sex peptide and its specific receptor expressed in the female oviduct sensory neurons are known to be crucial. However, the mechanism by which mating information is transmitted from sex peptide receptor-positive sensory neurons to germline stem cells at both molecular and cellular levels is largely unknown.

In this study, University of Tsukuba researchers in Japan; Yuto Yoshinari, Tomotsune Ameku, Yuko Shimada-Niwa, Professor Ryusuke Niwa, and their colleagues identified the neuronal mechanism that connects germline stem cells and sex peptide receptor-positive sensory neurons in the regulation of female D. melanogaster mating-induced germline stem cells increase. Their findings show that the germline stem cell increase in response to mating in female D. melanogaster is modulated by efferent octopaminergic neurons projecting to the ovary. The research work is published in the journal Elife.

The research team observed that the octopamine receptor, Octopamine receptor in mushroom body (Oamb) in ovarian escort cells was responsible for the regulation of mating-induced increase in germline stem cell. This mating-induced increase in germline stem cell was however found to be independent from the ovulation process. They also observed that mating caused the activation of the bone morphogenetic protein signal in germline stem cells, through Oamb in the escort cells, which resulted in an increase in germline stem cells. Octopamine signaling also regulated mating-induced increase in germline stem cell; it controlled Ca2+ signaling in escort cells, thereby inducing an increase in germline stem cells. Ovarian insect steroid hormones (ecdysteroids) signaling was found to be a requirement for octopamine-Oamb-Ca2+ signaling. Via Matrix metalloproteinase-2 and ecdysteroid signaling, the octopamine-Oamb signaling and the downstream Ca2+ signaling regulated mating-induced increase in germline stem cell. The neuronal activity of dsx+ Tdc2+ neurons that innervate the ovary and secrete octopamine mediate the mating-induced increase in germline stem cells. Sex peptide sensory neurons control the activity switch of dsx+ Tdc2+ neurons through acetylcholine signaling.

In summary, the authors have identified the octopaminergic neurons projecting to the ovary as new stem cell homeostasis modulators. Octopamine-like monoamines, such as noradrenaline, and steroid hormones observed in this study are also involved in stem cell regulation in mammals. This makes the reproductive system of D. melanogaster a preferred model to investigate the neuronal and systemic processes involved in stem cell homeostasis in animals.

Through this study, Professor Ryusuke Niwa and colleagues have been able to characterize mechanism through which neuronal system connects stem cell behavior to environmental signals such as mating through stem cell niche signaling. They have proposed a new efferent neuronal pathway that facilitates the transmission of mating stimulus to germline stem cells to regulate stem cell number.

A monoamine neurotransmitter regulates stem cells: A lesson from the fruit fly Drosophila melanogaster - Medicine Innovates

About the author

Ryusuke Niwa is a Professor of the Physiological Dynamics research project in the Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba, Japan. He is also a Visiting Professor of the High Energy Accelerator Research Organization (KEK), Japan. Since 2008 when he started his own laboratory, the major aim of his laboratory is to elucidate the neuroendocrine system and interorgan communication mechanism to regulate development and physiology. He has mainly using Drosophila and studied ecdysone biosynthesis, germline stem cell proliferation, energy homeostasis, reproductive dormancy, host-parasitoid wasp interaction, and chemical biology of pesticides.

Dr. Niwa is currently board members of the Molecular Biology Society of Japan and the Japanese Society of Developmental Biologists, and one of the organizing committee members of the International Insect Hormone Workshop. He is also editorial board members of Frontiers in Endocrinology (the section of Experimental Endocrinology), Development Growth and Differentiation, Fly, Genes to Cells, Insects, and Scientific Reports.


Yoshinari Y, Ameku T, Kondo S, Tanimoto H, Kuraishi T, Shimada-Niwa Y, Niwa R. Neuronal octopamine signaling regulates mating-induced germline stem cell increase in female Drosophila melanogaster. Elife. 2020;9:e57101.

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