Fellow's research: In a fruit fly, Lar decides 'to listen or not to listen to insulin signaling'
06 Feb 2020
Lolitika Mandal, Senior Fellow, Indian Institute of Science Education and Research, Mohali
Our recently published study shows how insulin signaling is regulated for the maintenance of the blood-forming stem like cells by a protein called Lar, in a fruit fly model.
Insulin is majorly known to be involved in regulating the nutritional status of an organism. Deregulated insulin signaling results in various diseased conditions like diabetes, infection, cancer, etc. Furthermore, the well-being of multiple tissues is also dependent on insulin signaling in both invertebrates and mammals.
In fruit fly larval blood-forming organ (the lymph gland), insulin signaling is essential for the maintenance of stem-like precursor cells and its microenvironment (niche). Due to the open circulatory system of the fruit fly, each cell type receives an equal shower of this systemic signal. We wondered whether different cell types within an organ is capable of tuning in or out from this ongoing shower of insulin signal? And, if so, how do they achieve this feat, which demands the integration of systemic factors with the local elements at tissue/cellular level.
Our recent work in fruit fly or Drosophila model shows that the blood stem cell niche expresses Lar (leucocyte antigen like protein). Lar acts like a rheostat controlling the exposure of the niche cells to insulin signaling, thereby subtly controlling their proliferation and function. Loss of Lar protein from niche hyperactivated insulin signaling, which in turn results in the generation of reactive oxygen species (ROS). This oxidative stress evokes an immune response in an otherwise healthy individual.
Our genetic as well as biochemical data demonstrates that Lar and Insulin Receptor (InR) physically interacts, and unravels the novel role of Lar in the stem cell compartment. The Drosophila hematopoietic niche harbors both naïve blood cells as well as primed blood cells that can respond to physiological changes or challenges that the animal may face. We show that Lar empowers the niche to gauge the physiological state of an animal and pass the necessary instruction to the stem-like progenitors.
It is established that diabetic mice with altered insulin signaling are known to have compromised hematopoietic niche. Whether Lar is also present in vertebrate hematopoietic niche/s and is required to control insulin-signaling remains to be explored.
Lar maintains the homeostasis of the hematopoietic organ in Drosophila by regulating insulin signaling in the niche. Harleen Kaur, Shiv Kumar Sharma, Sudip Mandal, Lolitika Mandal. Development 2019 146: dev178202 doi: 10.1242/dev.178202 Published 23 December 2019