Lipid droplets in cells

Alex Gould : Developmental adaptations to malnutrition

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Developing humans and other animals survive moderate nutrient deprivation by decreasing their overall growth rate and body size. During this adaptation, the growth of certain critical organs, such as the brain, is protected or spared at the expense of others. For example, in humans, fetal nutrient restriction can result in asymmetric intrauterine growth restriction (IUGR), characterised by undersized neonates with relatively large brains. Although brain sparing has been well documented in mammals for over 50 years, the underlying molecular mechanisms remain unclear.

Work in our lab showed that brain sparing is present in Drosophila. We used the power of clonal analysis and other genetic techniques in Drosophila to show that CNS growth sparing during nutrient restriction involves the rewiring of nutrient sensing and TOR/PI3K signalling in neural stem cell-like progenitors called neuroblasts. This rewiring process is, however, only implemented at later stages of development.

We found that it requires the activity of a specific receptor tyrosine kinase, Anaplastic lymphoma kinase (Alk). Alk stimulates PI3K signalling in neuroblasts, regardless of whether dietary nutrients are present or absent. This is because glial cells of the neuroblast niche constitutively secrete the ligand for Alk, Jelly belly. Neuroblast divisions are thus freed from nutrient-dependent growth components such as Insulin-like peptides. We are currently searching for additional growth sparing mechanisms in the CNS and in other tissues.

In humans, Alk is an oncogene that is frequently hyperactivated in human large cell lymphomas, non-small cell lung cancers, neuroblastomas and other tumours. Alk is therefore a molecular link between the genetic networks driving selective tissue growth in brain sparing and in some cancers. We have established a mouse model for brain sparing at The Crick and are currently testing which brain sparing genes are functionally conserved between insects and mammals.