Drosophila Perlecan modulates FGF and Hedgehog signals to activate neural stem cell division

Abstract

Mutations in the Drosophila trol gene cause cell cycle arrest of neuroblasts in the larval brain. Here, we show that trol encodes the Drosophila homolog of Perlecan and regulates neuroblast division by modulating both FGF and Hh signaling. Addition of human FGF-2 to trol mutant brains in culture rescues the trol proliferation phenotype, while addition of a MAPK inhibitor causes cell cycle arrest of the regulated neuroblasts in wildtype brains. Like FGF, Hh activates stem cell division in the larval brain in a Trol-dependent fashion. Coimmunoprecipitation studies are consistent with interactions between Trol and Hh and between mammalian Perlecan and Shh that are not competed with heparin sulfate. Finally, analyses of mutations in trol, hh, and ttv suggest that Trol affects Hh movement. These results indicate that Trol can mediate signaling through both of the FGF and Hedgehog pathways to control the onset of stem cell proliferation in the developing nervous system.

Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling

“…2, 3, 40, and 58) and SHH-GLI signaling controls the behavior of precursors and of cells with stem cell properties in the mammalian brain (e.g., refs. 30, 59, and 60 and V. Palma, D. Lim, N. Dahmane, N., P.S., Y. Gitton, A. Alvarez-Buylla, A., and A.R.A., unpublished data) and in other tissues and species (61,62), prostate cancer might derive from inappropriate expansion of prostatic epithelial stem cell lineages caused by abnormal SHH-GLI function.…”

Two Distinct Sites in Sonic Hedgehog Combine for Heparan Sulfate Interactions and Cell Signaling Functions

“…The H-160 antibody was used as a loading control. (34) and vertebrate systems (23) suggested that by forming a multimeric complex with specific HSPGs, perlecan and glypican, the efficiency of Shh signaling could be facilitated. To confirm that hShhNC24II could interact with heparin, we initially used a small scale heparin affinity assay and verified the specificity in the presence of competing free heparin (data not shown).…”

Insights into neural stem cell biology from flies

“…In mammals, Perlecan is a component of basal membranes that interacts with other extracellular matrix proteins, growth factors and receptors, to regulate cellular signalling ( Voigt et al 2002;Park et al 2003). Loss-of-function mutations in hedgehog (hh) and branchless (bnl, an FGF homologue) dominantly enhance the neuroblast proliferation defect in a sensitized trol mutant background (Park et al 2003). Both Hh and human FGF-2 have been shown to physically interact with Trol in coimmunoprecipitation studies, and the addition of human FGF-2 to trol mutant brains in culture can restore wild-type levels of neuroblast proliferation (Park et al 2003).…”

“…Loss-of-function mutations in hedgehog (hh) and branchless (bnl, an FGF homologue) dominantly enhance the neuroblast proliferation defect in a sensitized trol mutant background (Park et al 2003). Both Hh and human FGF-2 have been shown to physically interact with Trol in coimmunoprecipitation studies, and the addition of human FGF-2 to trol mutant brains in culture can restore wild-type levels of neuroblast proliferation (Park et al 2003). Interestingly, it is known that FGF can also act as a mitogen for adult mammalian neural stem cells (reviewed by Doetsch 2003).…”

“…Interestingly, it is known that FGF can also act as a mitogen for adult mammalian neural stem cells (reviewed by Doetsch 2003). It has also been reported that during the first larval instar, when neuroblasts reactivate, trol is expressed over the surface of the larval brain (Park et al 2003). This would place Trol in close proximity to the superficially located neuroblasts.…”