MRC National Institute for Medical Research, London
Science for Health
The selfish brain
04 August 2011
A mechanism by which brain growth is preferentially protected when dietary nutrients are scarce has been revealed by NIMR scientists. The research is published in Cell.
The rate of growth during development is regulated in line with the availability of nutrients. Most animal species developing in the wild are subject to periods of nutrient deprivation and, to survive these, they protect the growth of critical organs at the expense of other tissues. For example, an inadequate maternal food supply or placental defects late in human gestation lead to intra-uterine growth restriction (IUGR) resulting in undersized newborns with relatively large heads. This is because the growth of the brain has been spared at the expense of other internal organs such as the liver and pancreas. Channelling energy resources selectively into protecting brain growth is an important part of the survival strategy of the developing foetus when nutrients are scarce. However, brain sparing and the associated failure of certain internal organs to grow properly in utero can also be linked, much later on in adult life, to metabolic problems such as insulin resistance, obesity and cardiovascular disease.
The molecular mechanisms underlying brain sparing during nutrient restriction have remained unclear in humans and in other animals. The fruit fly, Drosophila melanogaster, shares two-thirds of all human disease genes and is a useful model in medical research. Alex Gould (pictured together with first author Louise Cheng), from NIMR's Division of Developmental Neurobiology, has shown that Drosophila displays remarkably strong brain sparing during dietary restriction. Using the advanced genetic tools available in this model organism, and working with Paul Driscoll in the Division of Molecular Structure, he has for the first time identified a molecular network responsible for brain sparing.
If dietary nutrients are restricted at the late larval stage, net growth of the body shuts down completely but the brain sparing network allows neural stem cells to continue growing at close to 100% of their normal rate. The molecular network itself comprises proteins that are all highly conserved between flies and humans including components of the TOR Complex 1 (TORC1) and PI3-Kinase (PI3K) signalling pathways. A key regulator of these pathways is the receptor Anaplastic Lymphoma Kinase (Alk) which, together with its ligand Jelly Belly (Jeb), activates components of the TORC1/PI3K pathways without the usual obligate inputs from amino acid and Insulin/IGF signals. Thus, Alk promotes “selfish” brain growth by switching growing cells from their usual nutrient-sensitive state to a nutrient-blind one (see diagram below). This is thought to be the first time that this has been observed in any healthy cell type in a developing animal.
Brain sparing in the late-stage Drosophila larva
Click image to view at full-size
CNS stem cells (green) can grow during nutrient restriction (NR) while many other tissues (yellow) can not. Anaplastic Lymphoma Kinase (Alk) and its ligand Jelly Belly (Jeb) promote the growth of CNS stem cells during NR by bypassing the nutrient sensing inputs from amino acids and Insulin-like peptides (Ilps), both of which are necessary for the growth of other tissues.
It was a complete surprise to Gould to find that the molecule occupying centre stage in the growing fruit fly brain, Alk, also turns out to be a well known oncogene, critical for the growth of many different tumours. So it appears that Alk can give cells a growth advantage in contexts as diverse as human cancers and developing fruit fly brains.
This work establishes the conservation of brain sparing across the animal kingdom, establishes a new genetic model for human IUGR and promises to shed light on the intriguing puzzle of how the mother's diet impacts upon health and disease later on in adult life.
Alex Gould
Original article
Anaplastic Lymphoma Kinase Spares Organ Growth during Nutrient Restriction in Drosophila (2011)
Louise Y. Cheng, Andrew P. Bailey, Sally J. Leevers, Timothy J. Ragan, Paul C Driscoll and Alex P. Gould.
Cell, 146(3):435-447. Publisher abstract.
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