Abstract
The adaptable transcriptional response to changes in food availability not only ensures animal survival but also lets embryonic development progress. Interestingly, the CNS is preferentially protected from periods of malnutrition, a phenomenon known as “brain sparing.” However, the mechanisms that mediate this response remain poorly understood. To get a better understanding of this, we used Drosophila melanogaster as a model, analyzing the transcriptional response of neural stem cells (neuroblasts) and glia of the blood–brain barrier (BBB) from larvae of both sexes during nutrient restriction using targeted DamID. We found differentially expressed genes in both neuroblasts and glia of the BBB, although the effect of nutrient deficiency was primarily observed in the BBB. We characterized the function of a nutritional sensitive gene expressed in the BBB, the serine protease homolog, scarface (scaf). Scaf is expressed in subperineurial glia in the BBB in response to nutrition. Tissue-specific knockdown of scaf increases subperineurial glia endoreplication and proliferation of perineurial glia in the blood–brain barrier. Furthermore, neuroblast proliferation is diminished on scaf knockdown in subperineurial glia. Interestingly, reexpression of Scaf in subperineurial glia is able to enhance neuroblast proliferation and brain growth of animals in starvation. Finally, we show that loss of scaf in the blood–brain barrier increases sensitivity to drugs in adulthood, suggesting a physiological impairment. We propose that Scaf integrates the nutrient status to modulate the balance between neurogenesis and growth of the BBB, preserving the proper equilibrium between the size of the barrier and the brain.SIGNIFICANCE STATEMENT The Drosophila BBB separates the CNS from the open circulatory system. The BBB glia are not only acting as a physical segregation of tissues but participate in the regulation of the metabolism and neurogenesis during development. Here we analyze the transcriptional response of the BBB glia to nutrient deprivation during larval development, a condition in which protective mechanisms are switched on in the brain. Our findings show that the gene scarface reduces growth in the BBB while promoting the proliferation of neural stem, assuring the balanced growth of the larval brain. Thus, Scarface would link animal nutrition with brain development, coordinating neurogenesis with the growth of the BBB.
Highlights
The formation of the nervous system is a tightly regulated process that is controlled by complex mechanisms that mitigate external perturbations, such as temperature changes and food availability
A Drosophila brain-sparing model for understanding the response to nutrient restriction To understand the transcriptional response of the Drosophila blood–brain barrier (BBB) to NR, we established the brain-sparing model (Cheng et al, 2011; Contreras et al, 2018) under the temperature conditions required for performing polymerase II (PolII) targeted TaDa (Southall et al, 2013)
Scarface is expressed in subperineurial glia and is regulated by nutrient availability Because the growth of the BBB is affected by NR, we focused on BBB genes that were differentially expressed as indicated by our TaDa analysis
Summary
The formation of the nervous system is a tightly regulated process that is controlled by complex mechanisms that mitigate external perturbations, such as temperature changes and food availability. Brain development and function requires a microenvironment that is established and maintained by the blood–brain barrier (BBB), a selective barrier that separates the nervous system from the circulating blood. The inner layer, the SPG, forms septate junctions that block the passive movement of solutes across the BBB (Baumgartner et al, 1996; Carlson et al, 2000; Schwabe et al, 2005; Stork et al, 2008), controlling nutrient entry (Galagovsky et al, 2018) and the excretion of xenobiotic molecules (Tapadia and Lakhotia, 2005; Mayer et al, 2009; Hindle et al, 2017)
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