Pituitary adenylate cyclase-activating polypeptide is an autocrine inhibitor of mitosis in cultured cortical precursor cells

Lu, Nairu; DiCicco‐Bloom, Emanuel

doi:10.1073/pnas.94.7.3357

Cited by 173 publications

(174 citation statements)

References 38 publications

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“…Therefore, PACAP-PAC1 interactions could potentially play a role in growth cone motility and guidance in vivo. It would also be interesting to determine whether PACAP-PAC1 interactions provide an autocrine system for growth cone motility because some neurons have been shown to simultaneously express PACAP and its receptors (Lu and DiCicco-Bloom, 1997). It seems reasonable that an autocrine loop would likely promote the rate of neurite extension; potentially, asymmetric inhibition of autocrine PACAP-PAC1 interactions at the growth cone could also influence the direction of growth cone extension.…”

Section: Discussionmentioning

confidence: 99%

Direct cAMP Signaling through G-Protein-Coupled Receptors Mediates Growth Cone Attraction Induced by Pituitary Adenylate Cyclase-Activating Polypeptide

et al. 2003

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Developing axons are guided to their appropriate targets by environmental cues through the activation of specific receptors and intracellular signaling pathways. Here we report that gradients of pituitary adenylate cyclase-activating polypeptide (PACAP), a neuropeptide widely expressed in the developing nervous system, induce marked attraction of Xenopus growth cones in vitro. PACAP exerted its chemoattractive effects through PAC1, a PACAP-selective G-protein-coupled receptor (GPRC) expressed at the growth cone. Furthermore, the attraction depended on localized cAMP signaling because it was completely blocked either by global elevation of intracellular cAMP levels using forskolin or by inhibition of protein kinase A using specific inhibitors. Moreover, local direct elevation of intracellular cAMP by focal photolysis of caged cAMP compounds was sufficient to induce growth cone attraction. On the other hand, blockade of Ca 2ϩ , phospholipase C, or phosphatidyl inositol-3 kinase signaling pathways did not affect PACAP-induced growth cone attraction. Finally, PACAP-induced attraction also involved the Rho family of small GTPases and required local protein synthesis. Taken together, our results establish cAMP signaling as an independent pathway capable of mediating growth cone attraction induced by a physiologically relevant peptide acting through GPCRs. Such a direct cAMP pathway could potentially operate in other guidance systems for the accurate wiring of the nervous system.

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Section: Discussionmentioning

confidence: 99%

Direct cAMP Signaling through G-Protein-Coupled Receptors Mediates Growth Cone Attraction Induced by Pituitary Adenylate Cyclase-Activating Polypeptide

et al. 2003

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“…E14 rat cortical cells (10) were plated on poly-D-lysine (0.1 mg/ml)͞laminin (20 g/ml)-coated glass coverslips at 4-8 ϫ 10 4 cells/cm 2 in defined medium [Neurobasal͞B27 (from BRL), 2 mM glutamine, penicillin (25 units/ml), streptomycin (25 g/ml), BSA (0.1%)] with basic fibroblast growth factor (bFGF) (10 ng/ml). E16 sympathetic neuroblasts were seeded at 3 ϫ 10 4 cells per well (24-multiwell) (12).…”

Section: Methodsmentioning

confidence: 99%

“…After 4% paraformaldehyde fixation (20 min), immunocytochemistry was performed with antibodies to precursor markers vimentin and nestin [1:1000; developed by S. Hockfield and provided by Developmental Studies Hybridoma Bank (DSHB), University of Iowa, Iowa City], neuronal markers tau (1:10000; I. Fischer, Medical College of Philadelphia) and ␤III tubulin (1:1000; TuJ1, clone TU-20, Biogenesis, Poole, U.K.), astrocyte glial fibrillary acidic protein (GFAP, 1:1,000; Dako), oligodendrocyte marker Rip1 (1:1000, DSHB), and PAC1 (1:2500; A. Arimura, Tulane University, New Orleans) as described (10). Staining was visualized by using Vectastain ABC Kit or FITC-or Texas Red-conjugated secondary antibodies (1:100; Vector Laboratories).…”

Section: Methodsmentioning

confidence: 99%

“…Ligands for G protein-coupled receptors (GPCR) may play significant roles in neurogenesis in a regionally or developmentally specific fashion (6)(7)(8)(9). The neuropeptide PACAP (pituitary adenylate cyclase activating polypeptide ) exhibits either positive or negative mitogenic effects depending on the neuroblast (10)(11)(12). The basis of these opposite effects is undefined, but may be due to differential expression of PACAP receptor isoforms and consequent activation of distinct signal transduction pathways.…”

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confidence: 99%

“…In primary neuroblasts, we previously defined region-specific mitogenic effects of PACAP, which may be attributed to receptor isoforms (17). For example, in embryonic hindbrain (11) and cortical neuroblasts (10,17), which express the short variant, PACAP stimulates AC only and elicits mitotic inhibition. In contrast, in sympathetic neuroblasts, which express the hop variant, PACAP activates both AC and PLC pathways and stimulates precursor mitosis (12,17).…”

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Regulation of neuroblast mitosis is determined by PACAP receptor isoform expression

Nicot

DiCicco‐Bloom

2001

Proc. Natl. Acad. Sci. U.S.A.

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Although neurogenesis in the embryo proceeds in a region-or lineage-specific fashion coincident with neuropeptide expression, a regulatory role for G protein-coupled receptors (GPCR) remains undefined. Pituitary adenylate cyclase activating polypeptide (PACAP) stimulates sympathetic neuroblast proliferation, whereas the peptide inhibits embryonic cortical precursor mitosis. Here, by using ectopic expression strategies, we show that the opposing mitogenic effects of PACAP are determined by expression of PACAP receptor splice isoforms and differential coupling to the phospholipase C (PLC) pathway, as opposed to differences in cellular context. In embryonic day 14 (E14) cortical precursors transfected with the hop receptor variant, but not cells transfected with the short variant, PACAP activates the PLC pathway, increasing intracellular calcium and eliciting translocation of protein kinase C. Ectopic expression of the hop variant in cortical neuroblasts transforms the antimitotic effect of PACAP into a promitogenic signal. Furthermore, PACAP promitogenic effects required PLC pathway function indicated by antagonist U-73122 studies in hop-transfected cortical cells and native sympathetic neuroblasts. These observations highlight the critical role of lineage-specific expression of GPCR variants in determining mitogenic signaling in neural precursors.

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Structure and distribution of the mRNAs encoding pituitary adenylate cyclase-activating polypeptide and growth hormone-releasing hormone-like peptide in the frog,Rana ridibunda

et al. 2000

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The structure of the neuropeptide pituitary adenylate cyclase‐activating polypeptide (PACAP) has been characterized in several species including protochordates, fish, amphibians, birds, and mammals. Although PACAP has been shown to stimulate frog pituitary and adrenal cell activity, the structure of the PACAP precursor and the expression of its gene have not yet been reported in any amphibian species. In this study, we have characterized two cDNA variants encoding PACAP of the frog Rana ridibunda, one of which encodes a second peptide exhibiting strong homologies to growth hormone‐releasing hormone (GHRH) of fish and mammals. Northern blot and reverse transcriptase‐polymerase chain reaction (RT‐PCR) analyses revealed that PACAP/GHRH‐like peptide mRNAs are predominantly expressed in the brain and spinal cord and, to a lesser extent, in the neurointermediate lobe of the pituitary. Other tissues including the testis and the distal lobe of the pituitary do not express the PACAP precursor gene. The distribution of PACAP/GHRH‐like peptide mRNAs in the frog brain has been determined by in situ hybridization histochemistry. High levels of expression were found in the accessory olfactory bulb, the distal pallium, the ventral part of the magnocellular preoptic nucleus, the ventral hypothalamic nucleus, the posterior tuberculum, and the ventral habenular nucleus. These data contribute to the understanding of the evolution of the PACAP and GHRH genes in vertebrates and provide the anatomical bases to elucidate the roles of PACAP and the GHRH‐like peptide in amphibians. J. Comp. Neurol. 421:234–246, 2000. © 2000 Wiley‐Liss, Inc.

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Pituitary adenylate cyclase-activating polypeptide is an autocrine inhibitor of mitosis in cultured cortical precursor cells

Abstract: ABSTRACT

Cited by 173 publications

References 38 publications

Direct cAMP Signaling through G-Protein-Coupled Receptors Mediates Growth Cone Attraction Induced by Pituitary Adenylate Cyclase-Activating Polypeptide

Direct cAMP Signaling through G-Protein-Coupled Receptors Mediates Growth Cone Attraction Induced by Pituitary Adenylate Cyclase-Activating Polypeptide

Regulation of neuroblast mitosis is determined by PACAP receptor isoform expression

Structure and distribution of the mRNAs encoding pituitary adenylate cyclase-activating polypeptide and growth hormone-releasing hormone-like peptide in the frog,Rana ridibunda

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