Sci. Signal., 9 August 2011
Metabolism Spare the Brain
Science Signaling, AAAS, Washington, DC 20005, USA
In Drosophila, the growth-promoting phosphoinositide 3-kinase (PI3K) can be activated downstream of insulin-like peptide stimulation of the insulin-like receptor and also by amino acid–mediated stimulation of a pathway consisting of the GTPases RagA and Rheb and the kinase target of rapamycin (Tor). The imaginal discs and the central nervous system (CNS) are less sensitive to growth inhibition caused by restricted availability of nutrients that activate these pathways. Cheng et al. (see also Teleman) confirmed that severe nutrient restriction in Drosophila larvae curtailed the net growth of several internal organs, including the salivary gland, but the net growth of the wing imaginal disc and the CNS spared. Mosaic analysis of clones revealed that neuroblast proliferation in nutrient-restricted larvae was similar to that in fed larvae, whereas epithelial progenitors in the wing disc showed reduced proliferation in starved larvae. Manipulations that increased or decreased the secretion of insulin-like peptide 2 did not alter the size of the wing disc or the CNS. However, the size of wing disc clones, but not that of neuroblast clones, was decreased by partial or full genetic inactivation of Slimfast (which encodes an amino acid transporter located in the fat body), Rheb, or Tor. Neuroblast clone growth or number (or both) showed the expected increase or decrease upon loss-of-function mutations in downstream TOR effectors or targets of PI3K, suggesting that growth-promoting pathways were activated in neuroblasts independently of their normal growth stimuli. Neuroblast clonal growth and proliferation during late larval stages did not require the insulin-like receptor, but instead depended on the receptor tyrosine kinase Alk (anaplastic lymphoma kinase). Nutrient restriction reduced the volume and number of Alk neuroblast clones, a phenotype that could be rescued to differing extents by expression of constitutively active or wild-type p110 (the catalytic subunit of PI3K), Pdk1 (a downstream target of PI3K), and Akt1 (another downstream target of PI3K). RNA interference directed against the Alk ligand Jelly belly (Jeb) in glial cells reduced neuroblast clone volume and number, thus indicating that neuronal Alk is activated by Jeb secreted from glial cells. The salivary gland is usually subject to curtailed growth during nutrient restriction, and ectopic expression of Alk in the salivary gland conferred growth sparing. Thus, Alk in neuroblasts and Jeb produced by glial cells disengage signaling through insulin and amino acid–activated pathways from their normal inputs to ensure sparing of CNS growth during nutrient deprivation.
L. Y. Cheng, A. P. Bailey, S. J. Leevers, T. J. Ragan, P. C. Driscoll, A. P. Gould, Anaplastic lymphoma kinase spares organ growth during nutrient restriction in Drosophila. Cell 146, 435–447 (2011). [Abstract]
A. A. Teleman, Privileged signaling for brain growth. Cell 146, 346–347 (2011). [Abstract]
Citation: W. Wong, Spare the Brain. Sci. Signal. 4, ec220 (2011).
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