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Growing up on a low-protein diet

A representative field of larval neurons grown in culture.  Blue-nucleus, Green-neuroendocrine cell (others are neurons), Magenta-protein translation in the cells.

A representative field of larval neurons grown in culture. Blue-nucleus, Green-neuroendocrine cell (others are neurons), Magenta-protein translation in the cells.

Poor quality nutrition during pregnancy results in smaller sized babies; remarkably, not all body parts decrease in size to the same extent. In humans, the brain is accorded preference for growth and will develop to near-normal size - an observation made in the early 1970s and termed “brain sparing”. It may not be surprising that a normal-sized brain would be a developmental priority – after all, by controlling our choices and behavior, it’s the brain that helps us adapt in life.

How then does a developing brain cope with loss of nutritious food? The laboratory of Prof Gaiti Hasan at the National Centre For Biological Sciences has examined this question in fruit flies. In work recently accepted by the journal Development (, Hasan and colleagues focused on a special type of cell in the brain that secretes hormones, called neuroendocrine (NE) cells. Hormones made in NE cells influence feeding and metabolism, key processes required to integrate nutritional input to growth. Their article suggests that in NE cells, a calcium-based signalling can serve as an alternative system to help a protein-starved larvae survive to the pupal stage.

Flies go through distinct life stages - egg, larva, pupa and adult. As larva, they eat continuously to build up resources for the next developmental step, the pupa. “Our story began with mutant Drosophila fly that had impaired calcium signalling,” says Megha, an author of the work. “We noticed that the mutant was unable to transition from larva to pupa when deprived of proteins. Then, we began looking for which cell type or organ in the fly body was responsible for this. Our investigations led us to the neurons, amongst which, we decided to focus on the NE cells”, she adds. Working down from whole animal to a particular cell type, the study then focused on the molecular pathways inside the cell that connect protein metabolism to animal growth.

In a nutrient-rich condition, cells in a growing animal majorly use the insulin receptor based signaling pathway, to make proteins. When the animal is starved, nutrient-loss typically turns off insulin receptor signaling, in effect slowing down protein synthesis, in all the cells. However, in a developing animal, some tissues need to keep growing (Brain sparing), even when nutrition is reduced. The research report by Hasan’s group find that in flies, calcium-dependent signalling pathway controlled by Inositol 1,4,5-trisphosphate Receptor (IP3R) appears to compensate for reduced insulin receptor signalling in NE cells. That IP3R/calcium signaling can substitute at the level of protein metabolism is a new finding and represents a novel way to keep protein synthesis going, when nutrient-dependent insulin receptor signaling is lost.

“This study is a vignette that feeds into this bigger picture of brain sparing” says Megha. In the future she hopes to use the Drosophila system to understand how early life nutrition can affect adult brain function. “I think this can be a great way to gain insights into factors affecting intrauterine growth retardation and how early nutrition inputs, especially during gestation, can influence metabolism or mental health later in life,” she adds, chalking out how this study can be taken forward.